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Effect of the surface layer on drug release from delefilcon-A (Dailies Total1®) contact lenses
Accepted Manuscript Title: Effect of the surface layer on drug release from delefilcon-A (Dailies Total1® ) contact lenses Authors: Phillip Dixon, Anuj Chauhan PII: DOI: Reference:
S0378-5173(17)30544-6 http://dx.doi.org/doi:10.1016/j.ijpharm.2017.06.036 IJP 16760
To appear in:
International Journal of Pharmaceutics
Received date: Revised date: Accepted date:
22-2-2017 9-6-2017 12-6-2017
Please cite this article as: Dixon, Phillip, Chauhan, Anuj, Effect of the surface layer on drug release from delefilcon-A (Dailies Total1®) contact lenses.International Journal of Pharmaceutics http://dx.doi.org/10.1016/j.ijpharm.2017.06.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effect of the surface layer on drug release from delefilcon-A (Dailies Total1®) contact lenses
Phillip Dixon a, Anuj Chauhan b
Department of Chemical Engineering; University of Florida; 1030 Center Drive, Gainesville, FL 32611
a
email: [email protected]
b
Corresponding author: Tel: (352) 392 2592; fax: (352) 392 9513; email: [email protected]
2
Abstract: Contact lenses are receiving significant attention for delivering ophthalmic drugs with higher bioavailability compared to eye drops. Here we explore drug transport from delefilcon-A Dailies Total1® lenses which are designed to have a thin, high-water content layer on the surface. Our goal is to determine the impact of this high water content layer on drug transport for both hydrophobic (dexamethasone and cyclosporine) and hydrophilic (timolol and levofloxacin) drugs. Drugs were loaded into the lens by soaking in aqueous drug solutions till equilibrium, followed by release in phosphate buffered saline. The concentration data during release was fitted to the diffusion equation without considering the surface layer. If fits were poor, the surface layer was include in the model, as a burst release. Results showed that surface layer resulted in a burst release of about 35% of the loaded drug for the two hydrophilic drugs, and the model did not fit the data unless the surface layer was incorporated as a burst release. For the hydrophobic drugs, there was no burst release and the model fitted the data without including the surface layer likely because of the low partition coefficient of the hydrophobic drugs in the surface layer compared to the lens. The results further confirm the presence of the high water content surface layer on the Dailies Total1® lenses.
The release profile of the burst release for hydrophilic drugs could be
therapeutically useful for antibiotics where a high dose is desirable initially. The effect of vitamin E loading—an established procedure for increasing drug release time in other commercial lenses, was also tested on the release of timolol maleate and levofloxacin. A 20% vitamin E loading was found to increase the release time of timolol and levofloxacin by a factor of 5 and 3-fold respectively, but this increase proved much less effective compared to vitamin E’s effect on other commercial silicone hydrogels. Keywords: delefilcon-A lens Dailies Total1®, water gradient, drug delivery, timolol, dexamethasone, cyclosporine, levofloxacin
3 1
1. Introduction
2
Eye drops make up approximately 90% of all formulations for ophthalmic drugs in spite
3
of low bioavailability [1]. Only about 5% of the administered drug permeates cornea, with the
4
remaining 95% reaching systemic circulation, raising the potential of toxicity in key organs [2],
5
[3]. The low bioavailability of eye drops sometimes necessitates multiple eye drops each day,
6
which can reduce compliance [4]. Researchers have proposed soft contact lenses as an alternative
7
platform for ophthalmic drug delivery to significantly increase the bioavailability compared to eye
8
drops [5]. Initial attempts explored directly soaking hydrophilic lenses in a drug solution, but found
9
that unmodified contact lenses released the drug very quickly, in the order of a few minutes to an
10
hour. Recent work in this field has focused on control release from lenses through many
11
approaches including integration of particles, surfactant or vitamin E barriers into the lenses,
12
molecular imprinting, multi-layer structure and surface modifications [6-10]. The multi-layer
13
structure on its own or in combination with other approaches listed above could offer many
14
advantages for controlling the drug release profiles. For instance, a lens with a highly crosslinked
15
surface layer could reduce the high initial rates of drug release from the contact lenses, which may
16
be desirable to minimize the possibility of toxicity. Alternatively, a weakly crosslinked layer near
17
the surface could provide an increased initial release which could also be useful for some
18
indications such as infections, which require a high drug concentrations early on, followed by
19
reduced release rates. The surface layer could also offer additional benefits such as the possibility
20
of improved lubricity. For example, Alcon released a new lens ‘water-gradient’ lens in 2013
21
(delefilcon-A lens Dailies Total1®) to increase the surface lubricity [11]. This lens consists of an
22
80 µm silicon hydrogel core surrounded by a 10 µm high-water content layer. While the core has
23
a water content of approximately 33%, the outer layer has a water content of >80% [12]. While
4 24
the motivation for the development of this lens is for a higher lubricity and user comfort, the
25
surface layer could potentially be useful for obtaining desired drug release profiles from the lenses.
26
The effect of the surface layer on release profiles is expected to depend on the physical properties
27
of the drugs, particularly hydrophobicity. The surface layer may provide a burst for hydrophilic
28
drugs due to release from the high water content surface layer, and potentially provide a barrier to
29
hydrophobic drugs reducing the very high releases at short times.
30
Besides a lubricious layer, the release of drug from a contact lens can be changed by
31
modification to the lens [13-16]. As mentioned previously, unmodified contact lenses have a fast
32
release. For many drugs, the rapid release can have toxicity concerns [17-19]. Many approaches
33
have been proposed for increasing the release duration from contact lenses without sacrificing any
34
of the critical properties. Commercial contacts can be modified by incorporation of vitamin E
35
diffusion barriers into contact lenses to increase release durations of both hydrophilic and
36
hydrophobic drugs, as well as delivery multiple drugs simultaneously [20]. Vitamin E loaded
37
lenses have shown promise in in vitro experiments and in vivo animal studies on beagle models
38
with glaucoma [21]. These studies have used multiple brands of silicon hydrogels, such as
39
ACUVUE® TruEYETM or ACUVUE® Oasys®; however, none of these lenses have an outer
40
lubricious layer, which could be useful for a burst release combined with a secondary, longer
41
release of drug compared to an unmodified lens. We then explore the effect of vitamin E
42
incorporation on the Dailies Total1® to determine whether the vitamin E approach can be
43
integrated into the water gradient lens. Additionally, we expect vitamin E to partition only into
44
the core of the lens, so results from the vitamin E loaded lenses can be further useful in
45
understanding the role of the surface film on transport.
5 46
This paper examined four drugs, timolol maleate (beta blocker for treating glaucoma),
47
levofloxacin (antibiotic), dexamethasone (corticosteroid), and cyclosporine (anti-inflammatory),
48
and their release from the Dailies Total1® lens. These drugs consist of two hydrophilic, timolol
49
maleate and levofloxacin, and of two hydrophobic, dexamethasone and cyclosporine, to examine
50
the affinity of the outer layer. These four drugs have been studied in other lenses, but not in lenses
51
with the additional outer layer [11, 22-26]. The goal of this paper is to evaluate the diffusive
52
behavior of both hydrophilic and hydrophobic molecules through the dual layer lens in order to
53
better understand the effect of the high-water content surface layer on drug transport as well as see
54
if Dailies Total1® would be a good candidate for vitamin E loading as vitamin E loaded lenses
55
approach clinical human trials and eventually commercialization.
56
2. Materials and methods
57
2.1 Materials
58
Dailies Total1® lenses (diopter -8.00, delefilcon A, diameter 14.1mm) from Novartis were
59
used in this study. Timolol maleate (≥98%), levofloxacin (≥98%), and dexamethasone (≥98%)
60
were purchased from Sigma-Aldrich Chemicals (St. Louis, MO). Cyclosporine A (≥99%) was
61
purchased from LC Laboratories (Woburn, MA). Phosphate Bufferered Saline 1x without calcium
62
and magnesium (PBS) was purchased from Mediatech, Inc. (Manassas, VA). Ethanol (200 proof)
63
and Vitamin E (DL-alpha tocopherol, >96%) were purchased from Sigma-Aldrich. All chemicals
64
were used as received without further purification. Sodium Chloride was purchased from Fisher
65
Scientific.
66
2.2 Drug Solution Preparation
67
All drugs explored here are powders at room temperature. To maintain stability, the solid
68
drug, levofloxacin and dexamethasone were stored in a refrigerated at 4⁰C, cyclosporine A was
6 69
stored at -20⁰C, and timolol was stored at room temperature. All drug solutions were prepared by
70
weighing the mass (Denver Instrument, M-220D) and mixing with the required volume of PBS
71
(pH=7.4). The hydrophilic drugs dissolve easily but the hydrophobic drugs required longer stirring
72
times for complete dissolution (Table 1). Cyclosporine A and dexamethasone solutions were stored
73
in refrigerator in vials covered by aluminum foil to protect from degradation by long exposure to
74
ultraviolet light. Cyclosporine A was made at 25 μg/mL [26]. The heat of solution of cyclosporine
75
A is highly exothermic, allowing for solubility to increase with decreasing temperature. This
76
allows for this higher concentration of drug to be dissolved [27].
77
2.3 Drug Loading
78
The Dailies Total1® lenses were removed from their blister packs, rinsed with de-ionized
79
(DI) water, dabbed with a Kimwipe, and then placed in PBS overnight (12 hours) for storage. The
80
lens was then removed from the PBS, dabbed again with a Kimwipe, and placed in the drug
81
solution. The stock solution (Table 1) was used without further dilution except for cyclosporine
82
A, which was diluted to a drug concentration of 0.015 mg/mL to ensure that the solution was below
83
the solubility limit and would not experience any precipitation of drug.
84
The uptake of dexamethasone and cyclosporine could be monitored via UV-vis
85
spectrophotometry, allowing for determining when the lens reached equilibrium, which was
86
assumed after no change was detected in the loading concentration after 24 hours. The time the
87
lens reached 99.9% of this final concentration is taken as the equilibrium time. This point occurred
88
at approximately 13 and 30 hours for dexamethasone and cyclosporine respectively. The loading
89
times were roughly double of these equilibrium times to be sure that equilibrium can be assumed.
90
The uptake solutions for timolol and levofloxacin are too high to be measured for uptake, and the
91
small change in concentration would be difficult to read with dilutions. Previous studies of
7 92
hydrophilic drugs have used 24 hours as a benchmark for loading timolol maleate and levofloxacin
93
into contact lenses [22]. This loading duration was used for this study, and was found to be justified
94
when the release duration was much lower than 24 hours. The durations of the drug loading step
95
for each drug are listed in Table 2.
96
2.4 Drug Release
97
After the appropriate loading time, the lenses were removed from the solution, dabbed with
98
a Kimwipe to remove drug solution off the surface, and inserted into a blank 2 mL of PBS
99
(pH=7.4). Releases were run at ambient temperature. At specific time intervals, about 1.5 mL of
100
the release medium were withdrawn from the sample and placed into a quartz cuvette. The cuvette
101
was monitored using a UV-vis spectrophotometer (Thermospectronic Genesys 10 UV). The
102
absorbance was measured over a range of wavelengths, 270-315nm for timolol maleate, 265-
103
310nm for levofloxacin, 220-268nm for dexamethasone, and 208-220nm for cyclosporine A. After
104
measuring, the withdrawn solution was returned to the sample, so that the same solution was
105
maintained throughout the duration of the release.
106
2.5 Vitamin E Loading of Lenses
107
Commercial Dailies Total1® lenses were rinsed soaked in deionized water for 15 minutes
108
and then rinsed again with deionized water. The lenses were then soaked in a 3mL 44mg/mL
109
vitamin E-ethanol solution for 24 hours, which was determined to be adequate for equilibrium to
110
be reached between the lens and the solution. After the 24 hour period, the lenses are removed
111
from solution and left to dry for an additional 24 hours. After the drying period, the lenses were
112
rehydrated in PBS for 3 hours before being inserted into drug solution for uptake. The release of
113
drug from vitamin E loaded lenses followed the same procedure as unmodified lenses.
114
2.6. Transmittance measurement contact lens
8 115
The transmittance of Vitamin E laden lenses was measured using UV–vis spectrophotometer
116
(Thermospectronic Genesys 10 UV). The lenses were hydrated by soaking in PBS overnight, then
117
mounted on the outer surface of a quartz cuvette. The cuvette was placed in the spectrophotometer
118
and the transmittance values were measured at wavelengths ranging from 200 nm to 700 nm.
119
2.7 Ion Permeability measurement of contact lens
120
Lenses were soaked in 5 mL of a 1 M NaCl/DI H2O solution for 1 hour. Lenses were then
121
placed in 200 mL of DI H2O and monitored with a conductivity meter (OAKTON® CON 450).
122
The solution was constantly stirred at 100 rpm to keep solution well-mixed. Conductivity was
123
converted to molar concentration by measuring the conductivity of a known NaCl calibration
124
solution and using it as a conversion factor.
125
2.8 Diameter measurement of contact lens
126
Lenses were placed in a PBS solution and imaged with a digital camera. Images included
127
a ruler to determine the length per pixel ratio. Images were then analyzed in ImageJ to determine
128
diameters.
129
2.9 Data Analysis and Modeling
130
The collected spectra of release experiments were compared to a reference spectra to
131
determine the drug concentration. The measurement and the reference were compared in a Matlab
132
program using the ‘fminsearch’ function to give the ratio that gives the best fit between the two.
133
The wavelength range was used rather than a single point to ensure that there were no additional
134
absorbance contribution from any other components as well as ensuring that the drug spectra did
135
not change over the course of the experiment.
136
The ratio calculated from the Matlab program is then used to calculate the concentration of
137
the release medium. These concentration can then be multiplied by the release volume to determine
9 138
mass released. These mass released values can be divided by total mass loaded in the lens to give
139
percent release, which is the value used in plots of the releases.
140
The two main values used to quantify releases are partition coefficient, K, defined as the
141
ratio of the drug concentration in the gel and the concentration in the aqueous phase at equilibrium,
142
and diffusivity, D, which describes the resistance in the lens to the movement of drug. Partition
143
coefficient can be calculated from the equilibrium values of drug loading and release, and is
144
discussed in more detail in section 3.1 Diffusivity must be found by fitting a mathematical model
145
to the transient release data and minimizing the sum of squared error via Matlab ‘fminsearch,’
146
which is discussed in section 3.2 and 3.3. These sections describe a single layer model, a dual layer
147
with burst release model, and a numerical model for non-perfect sink conditions.
148
For the model fits, a correlation constant was calculated comparing the model value to the
149
experimental value. This value will be used when comparing different models to the experimental
150
data.
151
3. Results and Discussion
152
3.1 Partition Coefficient
153
The initial and final concentrations of the dexamethasone and cyclosporine A loading
154
solutions were measured to determine the amount of drug loaded into the lens (Table 4). The
155
concentration in the loading solution does not change significantly for the hydrophilic drugs so the
156
mass of the drug loaded in the lens could not be determined from the loading step. The amount of
157
drug taken up by the lens can be used to calculate the partition coefficient. The values of partition
158
coefficient can be obtained from both the loading and the release experiments. For the loading
159
experiment the partition coefficient can be calculated by
160
𝐾=
𝐶𝑔,𝑓 𝐶𝑙,𝑓
=
𝑉𝑙 (𝐶𝑙,𝑖 −𝐶𝑙,𝑓 ) 𝑉𝑔 𝐶𝑙,𝑓
(1)
10 161
where Vl and Vg are the volumes of the loading solution and the fully hydrated gel, respectively,
162
and Cg,f, Cl,i and Cl,f are the equilibrium concentrations of the drug in the gel, and the initial and
163
equilibrium concentrations in the loading solution. Eq. 1 is used for the calculation of the partition
164
coefficient of dexamethasone and cyclosporine.
165
The partition coefficient of hydrophilic drugs needs to incorporate the release, as the
166
loading concentration is too high to measure and remains relatively constant during loading. The
167
volume of the lens was significantly less than the volume of the loading and release media, and
168
with a high solubility limit, hydrophilic drugs can be assumed to be loading and releasing under
169
perfect sink conditions. This assumption assumes that the lens will release all of its loaded drug,
170
or in other words, that drug loaded yields drug released. Based on these assumptions, the partition
171
coefficient for hydrophilic drugs to be calculated using the following equation based on the release data:
172
𝐾=
173
where Vr and Cr,f are the volume and final concentration of the release medium, respectively. Eq.
174
2 is used to calculate the partition coefficients of timolol maleate and levofloxacin. The calculated
175
partition coefficients are listed in Table 3.
𝐶𝑔,𝑓 𝐶𝑤,𝑓
=
𝑉𝑟 (𝐶𝑟,𝑓 ) 𝑉𝑔 𝐶𝑙,𝑓
(2)
176
The Dailies Total1® lens comprise of an 80 microns thick silicone-hydrogel core with a
177
water content of 33% and an 11±4 microns thick surface layer with a water content of about 80%
178
[12]. It should be noted that, according to the product description, the aqueous concentration in the
179
outer layer is not uniform but is rather a gradient from the water concentration of inner core that
180
increases to near 100% water at the boundary layer with the bulk fluid. The measured partition
181
coefficients represent the volume average partition coefficients of the two layers. The partition
182
coefficient of hydrophobic drugs is typically larger than that for the hydrophilic drugs in silicone-
183
hydrogels because of the absorption of the drug molecules on the polymer. The high solubility of
11 184
the hydrophilic drugs results in low adsorption on the polymer, which results in a partition
185
coefficient comparable to the water content of the gel. The measured partition coefficients in
186
Dailies Total1® for levofloxacin and timolol are much smaller than those for dexamethasone and
187
cyclosporine (Table 3).
188
ACUVUE® OASYS® and ACUVUE® TruEyeTM. The partition coefficient for the Dailies
189
Total1® are of the same magnitude as the compared lenses, although the lens more closely matches
190
the hydrophobic drug behavior of TruEyeTM.
Table 3 also shows values of two other silicone hydrogel lenses,
191
Since the Dailies Total1® lens contains two distinct regions, the measured partition
192
coefficient is a combination of two separate partition coefficients. Assuming φ to be the volume
193
fraction of the surface layer based upon the ratio of thicknesses of the layers, or approximately
194
0.216 for Dailies Total1®, the partition coefficient can be described as
195
𝐾 = 𝐾1 (1 − 𝜑) + 𝐾2 𝜑
196
where K1 and K2 are the partition coefficient of the interior hydrogel and surface layer respectively.
197
As the surface layer has a high water-content, hydrophilic drugs with a low affinity for the polymer
198
matrix will mostly be in the water phase of the surface-film, matching the concentration of the
199
bulk solution. This assumption simplifies Eq. 4 by assuming K2=1 to give
200
𝐾 = 𝐾1 (1 − 𝜑) + 𝜑
201
For hydrophobic drugs, the low solubility of drugs in the aqueous phase suggests low drug
202
partitioning into the surface layer. As K1>> 𝜑 for hydrophobic drugs, this term can be ignored and
203
𝐾 = 𝐾1 (1 − 𝜑)
204
Discussion for the two region partition coefficients for timolol and levofloxacin will continue on
205
in the section on the burst release model.
206
3.2 Diffusivity
(3)
(4)
(5)
12 207
The release profile of all four drugs is shown in Figure 1, and a smaller time scale release
208
of timolol and levofloxacin are shown in Figure 2. These graphs are plotted as percent released,
209
which is the measured mass released divided by the total mass released. Timolol maleate and
210
levofloxacin, both highly hydrophilic drugs, reached 90% drug release within 15 to 20 minutes.
211
Dexamethasone and cyclosporine A, both hydrophobic drugs, had much longer release hours,
212
reaching 90% release at approximately 7 and 15 hours respectively. The slower diffusivity of the
213
hydrophobic drugs can be attributed to the higher partition coefficient of the drugs. The silicon
214
hydrogel used in contact lenses is a biphasic system, with hydrophilic and hydrophobic regions.
215
Drug inside the contact lens is either absorbed in the aqueous phase of the lens or adsorbed onto
216
the surface of the polymer matrix. While this affects the partition coefficient, as previously
217
discussed, the phase of the drug also affects its release time. After reaching equilibrium inside of
218
the loading solution, the drug inside of the lens also reaches an equilibrium between the adsorption
219
and desorption of drug on the polymer matrix. Upon release, drug exits the primarily through the
220
aqueous phase of the gel. As the aqueous concentration drops, the adsorption equilibrium is shifted,
221
and drug begins to desorb faster into the aqueous phase. This equilibrium between the adsorbed
222
and free drug is rapid, but the adsorbed drug must desorb to diffuse or diffuse along the surface
223
which is typically slower than bulk diffusion, thus reducing the flux of the drug, leading to
224
increased release duration. The diffusivity of a drug in the bi-phasic lens is a combination of the
225
diffusivities of the two different states, bulk diffusion of the free drug and surface diffusion of the
226
adsorbed drug. Considering these two fluxes separately in the convection diffusion equation yields
227
the following,
228
𝜕𝑐 𝜕𝑡
=
𝑓𝑎𝑞 𝐷𝑓 𝜕2 𝑐 𝐾
𝜕𝑦
+ 2
(𝐾−𝑓𝑎𝑞 )𝐷𝑠 𝜕2 𝑐 𝐾
𝜕𝑦 2
= 𝐷𝑒𝑓𝑓
𝜕2 𝑐 𝜕𝑦 2
(6)
13 229
where faq is the volume fraction of the aqueous phase, and Df and Ds are the diffusivities of drug
230
in solution and on the surface respectively. The effective overall diffusivity can be defined as the
231
combination of the two diffusivities based on the phase’s volume fraction of the lens, i.e.,
232
𝐷𝑒𝑓𝑓 =
𝑓𝑎𝑞 𝐷𝑓 +(𝐾−𝑓𝑎𝑞 )𝐷𝑠 𝐾
(7)
233
When release experiments are fitted to diffusion control model, the fitted diffusivity is the
234
effective diffusivity, which explains why the release durations for the hydrophobic drugs are
235
longer than those for hydrophilic drugs.
236
3.3. Models for Drug Release
237
To determine whether the surface layer impacts drug transport, the experimental data was
238
first fitted to a model that neglects the surface layer. The diffusion-control release from the
239
silicone-hydrogel core can be described by the 1-D diffusion equation,
240
𝜕𝐶 𝜕𝑡
=𝐷
𝜕2 𝑦 𝜕𝑦 2
(8)
241
where C is drug concentration in the gel, D is the effective diffusivity, t is time, and y is the
242
transverse coordinate (y = 0 is the center of the lens). The above equation implicitly neglects radial
243
transport because of the much larger radius compared to the thickness, and also assumes that the
244
transport can be described by using an average film thickness h instead of a position dependent
245
thickness. The diffusion equation can be solved subject to the following boundary and initial
246
conditions 𝜕𝐶
(𝑡, 𝑦 = 0) = 0
(9)
248
𝐶(𝑡, 𝑦 = ℎ) = 𝐾𝐶𝑟
(10)
249
𝐶(𝑡 = 0, 𝑦) = 𝐶𝑖
(11)
247
𝜕𝑦
14 250
where Ci is the initial drug concentration of the lens, h is half the thickness of the silicone-hydrogel
251
core, K is the partition coefficient and Cr is the drug concentration in the release medium. The first
252
boundary condition assumes symmetry at the center of the lens, while the second assumes
253
equilibrium at the boundary between the lens and the release medium. The concentration in the
254
release medium can be determined through a mass balance that equates the drug released by the
255
lens to accumulation in the fluid, i.e.,
256
𝑉𝑟
257
where As is the total surface area of the lens, including both sides.
𝑑𝐶𝑟 𝑑𝑡
𝜕𝐶
= −𝐷𝐴𝑠 𝜕𝑦|
(12)
𝑦=ℎ
258
For hydrophilic drugs, the partition coefficient is sufficiently small so a perfect sink
259
assumption can be used, which implies that the concentration in the release medium is negligible.
260
This assumption is reasonable in the release experiments because the volume of the release
261
medium (2 mL) was much larger than the volume of the lens (approximately 30μL) and the
262
partition coefficient was small. Under perfect sink assumption, the concentration in the lens and
263
the release medium are given by the following equations
264
𝑖 𝐶 = ∑∞ 𝑛=0 (2𝑛+1)𝜋 cos (
(−1)𝑛 4𝐶
(2𝑛+1)𝜋 2ℎ
𝑦) 𝑒
(2𝑛+1)2 𝜋2 16 𝐴𝑠 ℎ𝐶𝑖 − 𝐷𝑡 ∞ 4ℎ2 ∑𝑛=0 𝑒 𝑉𝑟 (2𝑛+1)2 𝜋 2
−
(2𝑛+1)2 𝜋2 𝐷𝑡 4ℎ2
(13)
265
𝐶𝑟 =
266
where As is the surface area of the lens, C is the concentration inside of the lens, Cr is the
267
concentration in the release medium, h is half the thickness of the lens, Vr is the volume of the
268
release medium, n is an integer, D is diffusivity, and t is time. This analytical solution can then be
269
fitted to the data by using the ‘fminsearch’ function to vary D, diffusivity, to minimize the error.
270
Concentration can be converted to percent released by dividing by the final concentration value
(14)
15
271
𝐶𝑟 (𝑡) 𝐶𝑟 (𝑡→∞)
= 𝑃𝑒𝑟𝑐𝑒𝑛𝑡 𝑅𝑒𝑙𝑒𝑎𝑠𝑒𝑑 = 1 −
8 𝜋2
∑
1 ∞ 𝑛=0 (2𝑛+1)2
𝑒
(2𝑛+1)2 𝜋2 𝐷𝑡 4ℎ2
−
(15)
272
where Cr(t→∞) is the final concentration of the release medium. This model is used to determine
273
the diffusivities of the non-burst release models for all four drugs. The initial guess for diffusivity
274
fitting was obtained by fitting the short time release profile to the following equation,
275
𝐶𝑟 (𝑡) 𝐶𝑟 (𝑡→∞)
=
2 ℎ
𝐷
√ (𝑡)1/2 𝜋
(16)
276
This model is valid when 𝑡 < ℎ⁄4𝐷𝑡 . The single layer models for timolol and levofloxacin are
277
shown in Figure 4 and Figure 7, and have correlation coefficients of 0.9643 and 0.9484 respectively
278
(Table 5).
279
3.3.1 Burst Release
280
For timolol maleate and levofloxacin, the best fits consistently undrepredict the fraction
281
release in the short time range, as seen in Figure 6. Furthermore, the short term data can be fitted
282
linearly to sqrt(t) but only with a non-zero intercept, suggesting a very rapid release of a fraction
283
of the drug, as the initial concentration of the release medium should be zero, giving a zero
284
intercept. To have a non-zero intercept then suggests a rapid, nearly instantaneous release. Since
285
Dailies Total1® contact lens has two distinct layers, the transport can be described by a two layer
286
system to account for this rapid, or burst release. The effective diffusivity in the outer layer in the
287
Dailies Total1® contact lens will likely be much higher than in the inner core because of the high
288
water content. Assuming that the diffusivity in the surface layer is comparable to that in the
289
solution, the time for release from the surface layer can be approximated to be about a second,
290
which is far too rapid for analytical measurements. Because of this rapid release of the timolol
291
maleate and levofloxacin, it is possible to model these releases as instantaneous release of the
292
portion of the drug loaded in the surface layer, followed by a diffusive-release from the core. The
16 293
extend of the burst release was obtained by fitting the data but the initial guess was assumed to be
294
21.6% based on the volume fraction of the surface layer compared to the entire lens [8]. To model
295
the remaining drug release, the mass of the burst is subtracted from subsequent measurements, and
296
the modified data points are then fitted to minimize the error. All of this is completed in Matlab
297
using a modified version of Equation 14 16𝑀(1−𝑓𝑚𝑜𝑑𝑒𝑙 ) − ∑∞ 𝑛=0 𝑉 (2𝑛+1)2 𝜋2 𝑒
(2𝑛+1)2 𝜋2 𝐷𝑡 4ℎ2
𝑀
298
𝐶𝑟 =
299
where fmodel is the volume fraction of the lens responsible for burst release and M is the total mass
300
released. fmodel can be taken to be a volume fraction as this model assumes an similar concentration
301
across both layers of the lens.
𝑤
+ 𝑓𝑚𝑜𝑑𝑒𝑙 𝑉
𝑤
(17)
302
The burst model plots for timolol and levofloxacin in Figure 5 and Figure 8 respectively.
303
As seen in Table 5, the correlation coefficients using the burst release are increased to 0.9966 and
304
0.9921 for timolol and levofloxacin respectively, improved from the single layer model. Compared
305
to lenses studied in other papers, such as ACUVUE® lenses (Table 7). Dailies Total1® has a much
306
faster release duration, suggesting that the material used in this lens offers a much lower resistance
307
to diffusion compared to other commercially available hydrogels [11, 22, 24-26]. When comparing
308
the drug release times, the order from fastest to slowest falls in order of increasing molecular
309
weight. While this mass difference offers an explanation for the difference between timolol
310
maleate and levofloxacin as well as dexamethasone and cyclosporine, the effect of molecular
311
weight is smaller than the effect of the affinity of the drug towards water, as evidenced by the ~40
312
times increase in release duration between levofloxacin and dexamethasone, both of which have
313
similar molecular weights. This ratio is comparable to the ratio of the partition coefficients, which
314
suggests that the reduced diffusivity of dexamethasone is due to binding, and that the surface
315
diffusivity of the bound dexamethasone molecules is low.
17 316
No burst release was observed in either the dexamethasone or cyclosporine releases. This
317
lack of a burst release supports the notion of low partitioning into the aqueous phase of the lens
318
and that the outer layer, with its high water content, would have a much smaller amount of drug
319
than the inner core. The lack of a burst release for the hydrophobic drugs also validates that the
320
observed burst release of the hydrophilic drugs is not due to excess drug left on the surface when
321
removing the lens from the loading solution. If this situation were true, then the hydrophobic drugs
322
would have also shown a large initial release. The surface layer also does not act as a barrier to
323
the drug transport because even though the partition coefficient is low in this layer, the diffusivity
324
is likely very large due to the high water content, and thus the product KD for this layer is still
325
much larger than that for the lens core. Values for KD of the inner core are shown in Table 8. The
326
percentage value for the burst release for hydrophilic drugs is also of interest. The outer layer
327
composes approximately 20% of the lens’s volume. The similarity of magnitude suggests that the
328
initial burst is exclusively from the outer layer. The fraction of the burst release can be used to
329
evaluate the partition coefficients calculated in Eq. 3 and 4. These can be expressed as
330
𝑓𝑐𝑎𝑙𝑐 = 𝐾
331
And if K2 is assumed to equal 1
332
𝑓𝑐𝑎𝑙𝑐 = 𝐾
333
These two equations can show if the treatment of the outer layer as water predicts the behavior of
334
the burst release. Calculations for fcalc for timolol and levofloxacin are shown in Table 6 and are
335
compared to fmodel from the burst release model of Eq. 17. The calculations assuming a K2=1
336
give a fractional burst release of 0.13 compared to the model predicted 0.16±0.1 for timolol and
337
0.30 versus 0.2±0.2 for levofloxacin, which is a reasonable agreement.
338
3.3.2 Numerical Model for Hydrophobic Drugs
𝐾2 𝜑 (1−𝜑)+𝐾 1 2𝜑
𝜑 1 (1−𝜑)+𝜑
(18)
(19)
18 339
When comparing the values of loading and release in Table 4, it can be seen that a sizeable
340
portion of the drug remains in the lenses after a release without replacing the release medium. In
341
order to model the release in terms of percent of loaded drug released (Figure 3), a non-perfect
342
sink must be assumed, which requires a numerical model. An intrinsic finite difference method
343
was used in Matlab to model the numerical equation
344
𝑡+1 𝑡+1 𝐶𝑦𝑡+1 − 𝐶𝑦𝑡 = (∆𝑦)2 /∆𝑡 (𝐶𝑦+1 − 2𝐶𝑦𝑡+1 + 𝐶𝑦−1 )
345
where t is time, y is position from center of lens, C is drug concentration, D if effective diffusivity,
346
and Δy and Δt are the node step and time step respectively. This numerical model used the mass
347
balance of Eq. 12 to set its boundary conditions, the initial concentration in the lens were
348
determined from the loaded drug, and the initial concentration in the release medium was set to
349
zero. This numerical model was allowed to optimize diffusivity, with the initial input coming from
350
fitting Eq. 15; however, no sizeable change (<1%) in diffusivity was found by switching to the
351
numerical model. The fits of the model are shown in Figure 9 and Figure 10 and is in agreement
352
with the experimental data, with a correlation coefficient of 0.9869 and 0.9943 for dexamethasone
353
and cyclosporine. As these fits assume a single layer, their accuracy suggests that the surface layer
354
does not significantly impact the drug transport for the hydrophobic drugs.
355
3.4 Vitamin E incorporation
𝐷
(20)
356
Vitamin E incorporation has been explored as an approach to increase the release duration
357
of drugs through creation of diffusion barriers in multiple brands of commercial contact lenses.
358
Previous studies have examined the effect of the swelling of the lens due to ethanol and the
359
integration of vitamin E [20, 22, 24-26]. These studies found that after returning the lens to de-
360
ionized water or PBS solutions, the 20% vitamin E lens returned within 5% of its original diameter.
361
Lens parameters such as ion permeability, and oxygen permeability were found to be above
19 362
required minimum values after loading at 30% vitamin E or lower, as shown in Table 9 [22]. This
363
maintaining of the lens properties has allowed lenses modified with vitamin E to be used in animal
364
studies and approved for Phase I human studies.
365
Vitamin E loading increases the hydrophobic fraction of the silicon hydrogel. Highly
366
hydrophilic molecules such as timolol or levofloxacin have difficulty partitioning into a vitamin E
367
phase, and as such, must diffuse around the vitamin E, increasing their release time. The vitamin
368
E barriers are expected to form at the interface of the hydrophilic and silicone phases in the lens
369
matrix, and so incorporation of vitamin E in the lens can be used as an indirect approach for
370
exploring the microstructure. The concentration of vitamin E in ethanol was selected based upon
371
previous studies, which used 40-45 mg/mL vitamin E loading to achieve a 20% loading. The dry
372
weight of the Dailies Total1® lenses increased by 20±2% compared to the control by soaking in
373
the ethanol containing 44mg/mL vitamin E, which is comparable to the vitamin E loading achieved
374
in other commercial lenses. This increase can be ascribed to the mass of vitamin E loaded in the
375
lens. The weight gain in the lens is proportional to the degree of swelling in ethanol. The vitamin
376
E loaded lenses remain transparent, which suggests that the aggregates are nanosized.
377
The release of timolol and levofloxacin vitamin E loaded Dailies Total1® lenses can be
378
seen in Figure 11 and Figure 12 respectively. Vitamin E incorporation increases the release
379
duration of timolol and levofloxacin to about an hour, or roughly a 5-fold and 3-fold increase in
380
release time which can be ascribed to the formation of the diffusion barriers in the core of the lens.
381
The partition coefficient decreases for both timolol and levofloxacin to 1.43 and 0.47 respectively,
382
which is probably due to the hydrophobic nature of the vitamin E; however, the high solubility of
383
both of these drugs means that a higher drug loading concentration would compensate in the loss
384
of the partitioning onto the lens. The release profiles from the vitamin E loaded lenses exhibit burst
20 385
release as well, but the magnitude is slightly reduced comparable to that in the control lens. The
386
slight reduction could be due to the reduced drug loading in the core. While this increase in release
387
time is promising for drug delivery, the magnitude of increase achieved with vitamin E loading is
388
much larger in other lenses such as ACUVUE® OASYS®, making these other lenses more
389
effective in delivering larger dosages of drug to the anterior of the eye, as the rapid release from
390
Dailies Total1® could lead to toxicity concerns. However, for antibiotics such as levofloxacin, the
391
burst release, followed by an additional hour long release, might prove to be highly effective.
392
3.5 Effect of vitamin E on contact lens
393
Figure 13 shows that the decrease in transmittance due to vitamin E loading was almost
394
exclusively in the UV region, with the visible range maintaining a transmittance of greater than
395
88%. Figure 14 shows a digital image of both a control and modified lens, showing both the
396
maintained transmittance in the visible light range as well as the similar size of the two lenses.
397
Table 9 shows that the vitamin E loading yielded a 2.6% increase in lens diameter, putting in line
398
with other commercial lenses which see an increase of 3-4% [22]. This small increase means that
399
the curvature of the lens should remain largely unaffected. The hydrophobic nature of vitamin E
400
decreased the ion permeability of the Dailies Total1® lens, as seen in Table 9.
401
Oxygen permeability was not evaluated for Dailies Total1® lenses. However, past studies
402
have looked at other commercial lenses such as ACUVUE® OASYS® and O2 OptixTM showed
403
that vitamin E loading led to a small decrease in oxygen permeability but that the value was still
404
higher than the required 70 barrer to prevent hypoxia [22]. As Dailies Total1® has a higher oxygen
405
permeability than either of these lenses at a value of 156 barrer, it can be expected to stay above
406
the minimum required value at 20% vitamin E loading. Another lens parameter that was not
407
characterized was protein adherence. Future study will be needed to quantify vitamin E’s effect,
21 408
but the protein adherence should decrease as the diffusion rate of the proteins should decrease in
409
the lens.
410
4. Conclusions
411
The presence of the thin high water content surface layer has a significant impact on the drug
412
release profiles for hydrophilic drugs. The drug incorporated in the surface layer diffuses out
413
rapidly for both timolol maleate and levofloxacin. The duration of this rapid release was far too
414
short for measurements so it was included in the transport model as a burst release. The
415
experimental data showed a good fit with a diffusion control model, but only after the release
416
from the surface layer was included as a burst. The partition coefficient of the hydrophilic drugs
417
in the outer layer is close to one which is expected due to the very high water content. The
418
presence of the burst further validates the reported structure of the high water content surface
419
film in Dailies Total lenses. The burst release could be clinically useful for antibiotics, but may
420
be undesirable for other indications. The absence of the initial burst for dexamethasone and
421
cyclosporine A show that the outer layer has very low affinity for the hydrophobic drugs due to
422
the very low polymer fraction in the layer. Overall, the release duration from the Dailies Total1®
423
lens is less compared to other commercial lenses such as ACUVUE® OASYS® and ACUVUE®
424
TryEye®. Vitamin E incorporation can increase the release duration and decrease the initial burst
425
slightly. The release duration of the hydrophilic drugs may be far too short, but the release
426
duration for hydrophobic drugs is sufficient as a daily disposable modality. Studies on the effect
427
of vitamin E loading showed it to have minimal effect on transmittance and diameter of the lens,
428
while ion permeability was kept above the required limit for eye movement. Future work is
429
needed to characterize the effect of vitamin E loading on Dailies Total1® lenses oxygen
22 430
permeability and protein adherence before human use, but previous work on other commercial
431
contact lenses indicates that lens parameters should still be within required limits. 5. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems. Prog Retin Eye Res 1998;17(1):33–58 Mitra AK, editor. Ophthalmic drug delivery systems. New York, NY: Marcel Dekker, Inc.; 1993. p. 60 Segal P. Pumps and timed release. FDA Consumer Magazine; October 1991 N.P. Jones, R.J. Postlethwaite, J.L. Noble, Clearance of corneal crystals innephropathic cystinosis by topical cysteamine 0.5-percent, Br. J. Ophthalmol. 75 (1991) 311–312. Chi-Chung Li and Anuj Chauhan, Modeling Ophthalmic Drug Delivery by Soaked Contact Lenses, Ind. Eng. Chem. Res. 2006, 45, 3718-3734. Venkatesh S, Sizemore SP, Byrne ME. Biomimetic hydrogels for enhanced loading and extended release of ocular therapeutics. Biomaterials 2007;28:717–24. Hiratani H, Alvarez-Lorenzo C. The nature of backbone monomers determines the performance of imprinted soft contact lenses as timolol drug delivery systems. Biomaterials 2004;25:1105–13. Hiratani H, Mizutani Y, Alvarez-Lorenzo C. Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities. Macromol Biosci 2005;5:728–33. Alverez-Lorenzo C, Hiratani H, Gomez-Amoza JL, Martinez-Pacheco R, Souto C, Concheiro A. Soft contact lenses capable of sustained delivery of timolol. J Pharm Sci 2002;91:2182–92. Hiratani H, Alvarez-Lorenzo C. Timolol uptake and release by imprinted soft contact lenses made of N, Ndiethylacrylamide and methacrylic acid. J Control Release 2002;83:223–30. Pruitt J, Bauman E. The Development of Dailies Total1 Water Gradient Contact Lenses, Optometric Management 2013:9 T.J. Dursch, D.E. Liu, Y. Oh, C.J. Radke, Fluorescent solute-partitioning characterization of layered soft contact lenses, Acta Biomaterialia 2015:15:54-48 Hillman JS. Management of acute glaucoma with pilocarpine-soaked hydrophilic lens. Br J Ophthalmol 1974;58:674–9. Ruben M, Watkins R. Pilocarpine dispensation for the soft hydrophilic contact lens. Br J Ophthalmol 1975;59:455–8. Arthur BW, Hay GJ, Wasan SM, Willis WE. Ultrastructural effects of topical timolol on the rabbit cornea – outcome alone and in conjunction with a gas permeable contact-lens. Arch Ophthalmol 1983;101:1607–10. Wilson MC, Shields MB. A comparison of the clinical variations of the iridocorneal endothelial syndrome. Arch Ophthalmol 1989;107:1465–8. Schultz CL, Nunez IM, Silor DL, Neil ML. Contact lens containing a leachable absorbed material. US Patent No. 5723131, 1998. Schultz CL, Mint JM. Drug delivery system for antiglaucomatous medication. US Patent No. 6410045, 2002. Karlgard C,Wong NS, Jones L, Moresoli C. In vitro uptake and release studies of ocular pharmaceutical agents by silicon-containing and p-HEMA hydrogel contact lens materials. Int J Pharm 2003;257:141–51. Hsu, K.H., Fentzke, R.C., Chauhan, A., 2013. Feasibility of corneal drug delivery of cysteamine using vitamin E modified silicone hydrogel contact lenses. Eur J Pharm Biopharm 85, 531-540. Peng, CC, A. Ben-Shlomo, E. O. Mackay, C. E. Plummer, and A. Chauhan. "Drug Delivery by Contact Lens in Spontaneously Glaucomatous Dogs." Current Eye Research 37.3 (2012): 204-11. Cheng-Chun Peng, Jinah Kim, Anuj Chauhan, Extended delivery of hydrophilic drugs from siliconehydrogel contact lenses containing Vitamin E diffusion barriers, Biomaterials 31 (2010) 4032–4047 Jinah Kim, Anuj Chauhan, Dexamethasone transport and ocular delivery from poly(hydroxyethyl methacrylate) gels, International Journal of Pharmaceutics 353 (2008) 205–222 Paradiso, P., A. P. Serro, B. Saramago, R. Colaço, and A. Chauhan. "Controlled Release of Antibiotics From Vitamin E Loaded Silicone-Hydrogel Contact Lenses." Journal of Pharmaceutical Sciences 105.3 (2016): 1164-172.
23 25. Jinah Kim, Cheng-Chun Peng, Anuj Chauhan, Extended release of dexamethasone from silicone-hydrogel contact lenses containing vitamin E, Journal of Controlled Release 148 (2010) 110–116 26. Peng, CC, and A. Chauhan. "Extended Cyclosporine Delivery by Silicone-hydrogel Contact Lenses." Journal of Controlled Release 154.3 (2011): 267-74 27. Ismailos, G., Reppas, C., Dressman, J. B. and Macheras, P. (1991), Unusual solubility behaviour of cyclosporin A in aqueous media. Journal of Pharmacy and Pharmacology, 43: 287–289. 28. Nicolson P, Baron RC, Chabrecek P, Court J, Domscheke A, Griesser HJ, et al.Extended wear ophthalmic lens. US Patent No. 5760100, 1998. 29. Holden B, Mertz G. Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses. Invest Ophthalmol Vis Sci 1984;25:1161–7.
Tables & Figures Table 1: Composition, and preparation and storage conditions for the stock solutions Drug Timolol maleate Levofloxacin Dexamethasone Cyclosporine A
Stock Concentration (mg/mL) 1.5 5.0 0.05 0.025
Mixing Time (hrs) 1 1 3 24
Solution Storage Temperature (°C) Room Room 4⁰C 4⁰C
Table 2: Summary of composition and methods for the drug loading Drug
Loading Concentration (mg/mL)
Timolol maleate Levofloxacin Dexamethasone Cyclosporine A
1.5 5.0 0.05 0.015
Loading Solution Volume (mL) 3 3 4 10
Loading Time (hrs)
Solution Storage Temperature (°C)
24 24 48 72
Room Room 4⁰C 4⁰C
Table 3: Partition Coefficients in Dailies Total and comparison with previously reported partition coefficients in other commercial contact lenses Drug Dailies Total1® Partition 1-Day ACUVUE® ACUVUE® Coefficient TruEyeTM Oasys® Timolol maleate 1.60±0.11 --1.661 Levofloxacin 0.78±0.07 0.74±0.112 0.58±0.092 Dexamethasone 43.46±3.74 --105.703 Cyclosporine 160.80±7.55 31.60±10.34 485.0±30.24 1-[23], 2-[25], 3-[24], 4-[26] Data is shown as Mean ± Std (N = 6)
24 Table 4: Mass Uptake and Release of Dailies Total1® Loading Molecular Weight1 Drug Conc. (g/mol) (mg/mL) Timolol maleate 1.5 316 Levofloxacin 5.0 361 Dexamethasone 0.05 392 Cyclosporine 0.015 1202 1-From manufacturer Data is shown as Mean ± Std (N = 6)
Mass Uptake (μg)
Mass Released (μg)
----80.0±2.2 48.3±2.9
37.1±2.0 60.6±4.4 35.4±0.5 8.4±0.9
Table 5: Diffusion Coefficient (units m2/s) and Correlation Constants for different models: Single Correlation Layer Constant Diffusivity R2 Timolol 1.79E0.9643 maleate 12±8E-14 Levofloxacin 1.77E0.9484 12±2E-14 Dexamethasone --Cyclosporine --Data is shown as Mean ± Std (N = 6) Drug
Burst Release Diffusivity 1.53E12±8E-14 1.25E12±2E-14 -----
Correlation Constant R2
Numerical, NonPerfect Sink Diffusivity
0.9966
---
0.9921
--9.98E-14 3.19E-14
Table 6: Burst Release Partition Coefficient and fractional releases Drug K K1 (K2=1)1 f calc2 f model3 K1 (K2≠1) K2 Timolol 1.60 1.77 0.13 0.16 1.71 1.18 Timolol (20% vitamin E) 1.43 1.55 0.15 0.16 1.53 1.07 Levofloxacin 0.78 0.63 0.30 0.25 0.68 0.82 1-K1 indicates inner core, K2 indicates outer core; 2-From Eq. 17; 3-From Eq. 18 and 19 Table 7: Comparison of Release times (90% total mass released) Drug Dailies Total1® 1-Day Acuvue TruEye Acuvue Oasys Timolol maleate 0.2 hrs ---1.5 hrs1 Levofloxacin 0.2 hrs 33.3 hrs2 8.3 hrs2 Dexamethasone 8 hrs ---40 hrs3 Cyclosporine 18 hrs 25 hrs4 >20 days4 1-[23]; 2-[25]; 3-[24]; 4-[26]
Table 8: Calculated Permeability of inner silicone core K (inner core) D (m^2/s) KD (m^2/s) Timolol maleate 1.71 1.53E-12 2.62E-12 Levofloxacin 0.68 1.25E-12 8.50E-13 Dexamethasone 43.46 9.98E-14 4.34E-12 3.19E-14 Cyclosporine 160.80 5.13E-12
Correlation Constant R2
0.9869 0.9943
25
Table 9: Effect of vitamin E loading
Parameter Ion Permeability (mm2/min)
Minimum Value 6.00E-063
Dailies Total1® 4.92E-04
20% Vitamin E 7.94E-05
Diameter1 (cm)
---
1.412±0.007 ACUVUE OASYS®
Oxygen permeability2 (barrer)
874
120±18
1.449±0.011 20% Vitamin E 110±20
permeability2
874
O2 Optix Oxygen
(barrer)
20% Vitamin E 103±17
112±23
1- Dailies Total1® manufacturer value = 1.41 cm 2- from [22]; 1 barrer = 10-11 (cm2/s)(mLO2/mL mmHg)) 3- [28] 4- [29]
Percent Released
100%
80% 60%
Cyclosporine A
40%
Timolol Maleate Levofloxacin
20%
Dexamethasone
0% 0
5
10
15
20
25
30
Time (hr)
Figure 1: Release profile of four drugs from Dailies Total1®. Percent Release is defined as the ratio of the drug released at any time divided by the maximum mass of drug release. For hydrophilic drugs, a majority of the drug is released but for the hydrophobic drugs, a significant portion remains in the lens after equilibrium is reached. Data is shown as Mean ± Std (N = 6)
26
100%
Percent Released
80% 60% 40% Timolol Maleate
20% Levofloxacin
0% 0
0.1
0.2
Time (hr)
0.3
0.4
0.5
Figure 2: Release profiles of timolol maleate and levofloxacin. Percent release is calculated as the ratio of drug released at any time and that released at equilibrium. Data is shown as Mean ± Std (N = 6)
Percent Loaded Mass Released
27
50% 40% 30% 20% 10%
Dexamethasone Release Cyclosporine Release
0% 0
5
10
Time (hr)
15
20
25
Figure 3: Release profiles of dexamethasone and cyclosporine. The y-axis represents the ratio of drug released from the lens and that loaded in the lens during drug loading. A significant portion of the loaded drug is retained in the lens after equilibrium is reached. Data is shown as Mean ± Std (N = 6)
Percent Loaded Mass Released
28
100% 80% 60% 40% Timolol Maleate
20% Analytical Best Fit
0% 0.00
0.10
0.20
0.30
0.40
Time (hr) Figure 4: Comparison of the timolol release profiles and the best fit based on a single-layer diffusion control model under sink conditions (Eq. 15). Data is shown as Mean ± Std (N = 6).
0.50
Percent Loaded Mass Released
29
100% 80% 60% 40% Timolol Maleate
20%
Burst
0% 0.00
0.10
0.20
0.30
0.40
0.50
Time (hr) Figure 5: Comparison of the timolol release profiles and the best fit based on a diffusion control model under sink conditions including a burst release from the surface layer (Eq. 17). Data is shown as Mean ± Std (N = 6)
30
Residual Error
a
0.04 0.00
0
0.1
0.2
0.3
0.4
0.5
-0.04 -0.08
Single Layer Model Burst Release Model
-0.12
Residual Error
b
Time (hr)
0.08 0.04
0.00
0.00
0.10
0.20
0.30
0.40
0.50
-0.04 -0.08 -0.12 -0.16
Single Layer Model Burst Release Model
Time (hr)
Figure 6: Residual Error plots for fitting of the (a) timolol maleate and (b) levofloxacin experimental data with single layer model (blue) and the model after including burst (orange).
31
Percent Loaded Mass Released
100%
80%
60%
40% Levofloxacin 20% Analyticl Fit 0%
0.00
0.10
0.20
0.30
0.40
0.50
Time (hr) Figure 7: Comparison of the levofloxacin release profiles and the best fit based on a single-layer diffusion control model under sink conditions (Eq. 15). Data is shown as Mean ± Std (N = 6).
Percent Loaded Mass Released
32
100% 80% 60% 40% Levofloxacin
20% Burst Model
0% 0.00
0.10
0.20
0.30
0.40
0.50
Time (hr) Figure 8: Comparison of the levofloxacin release profiles and the best fit based on a diffusion control model under sink conditions including a burst release from the surface layer (Eq. 17). Data is shown as Mean ± Std (N = 6).
Percent Mass Loaded Released
33
50% 40% 30% 20% 10%
Non-perfect Sink Fit Dexamethasone Release
0%
0
4
8
12
16
20
Time (hr) Figure 9: Comparison of the dexamethasone release profiles and the best fit based on a numerical single-layer diffusion control model (Eq. 20). Data is shown as Mean ± Std (N = 6).
34
Percent Loaded Mass Released
20%
15%
10%
Non-perfect Sink Fit
5%
Cyclosporine Release
0% 0
5
10
15
20
25
30
35
Time (hr) Figure 10: Comparison of the cyclosporin A release profiles and the best fit based on a single-layer diffusion (Eq. 20). Data is shown as Mean ± Std (N = 6).
35
100%
Percent Released
80% 60% 40% 0% Vitamin E
20%
20% Vitamin E
0% 0.00
0.40
0.80
1.20
1.60
Time (hr) Figure 11: Effect of vitamin E incorporation on release of timolol maleate from Dailies Total1® lens. Data is shown as Mean ± Std (N = 6) for 0% vitamin E and (N=3) for 20% vitamin E.
36
100%
Percent Released
80% 60% 40% 20%
0% Vitamin E 20% Vitamin E
0%
0.00
0.40
0.80
Time (hr)
1.20
Figure 12: Effect of vitamin E incorporation on release of levofloxacin from Dailies Total1® lens. Data is shown as Mean ± Std (N = 6) for 0% vitamin E and (N=3) for 20% vitamin E.
37
100%
Transmittance
80%
60%
40% Dailies TOTAL1 20% vitamin E Loaded Dailies TOTAL1
20%
0% 200
300
400
500
600
700
Wavelength (nm) Figure 13: Transmittance spectrum of Dailies Total1® and Dailies Total1® with 20% vitamin E loading.
A
B
Figure 14: Image of unmodified (left side of image) and 20% vitamin E loaded (right side of image) Dailies Total1® with no dye (image A) and Nile blue dye (image B) for better visualization
*Graphical Abstract (for review)
Levofloxacin
100% 80%
60% 40% 20% 0% 0.00
0.10
0.20
0.30
0.40
0.50
Time (hr)
Percent Loaded Mass Released
Percent Loaded Mass Released
Timolol Maleate 100% 80% 60% 40% 20% 0% 0.00
0.10
0.30
0.40
0.50
Time (hr)
Dexamethasone…
Cyclosporine…
50%
20%
40%
Percent Loaded Mass Released
Percent Mass Loaded Released
0.20
15%
30%
10%
20%
10% 0% 0
4
8
12
Time (hr)
16
20
5%
0% 0
5
10
15
20
Time (hr)
25
30
35
S0378-5173(17)30544-6 http://dx.doi.org/doi:10.1016/j.ijpharm.2017.06.036 IJP 16760
To appear in:
International Journal of Pharmaceutics
Received date: Revised date: Accepted date:
22-2-2017 9-6-2017 12-6-2017
Please cite this article as: Dixon, Phillip, Chauhan, Anuj, Effect of the surface layer on drug release from delefilcon-A (Dailies Total1®) contact lenses.International Journal of Pharmaceutics http://dx.doi.org/10.1016/j.ijpharm.2017.06.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effect of the surface layer on drug release from delefilcon-A (Dailies Total1®) contact lenses
Phillip Dixon a, Anuj Chauhan b
Department of Chemical Engineering; University of Florida; 1030 Center Drive, Gainesville, FL 32611
a
email: [email protected]
b
Corresponding author: Tel: (352) 392 2592; fax: (352) 392 9513; email: [email protected]
2
Abstract: Contact lenses are receiving significant attention for delivering ophthalmic drugs with higher bioavailability compared to eye drops. Here we explore drug transport from delefilcon-A Dailies Total1® lenses which are designed to have a thin, high-water content layer on the surface. Our goal is to determine the impact of this high water content layer on drug transport for both hydrophobic (dexamethasone and cyclosporine) and hydrophilic (timolol and levofloxacin) drugs. Drugs were loaded into the lens by soaking in aqueous drug solutions till equilibrium, followed by release in phosphate buffered saline. The concentration data during release was fitted to the diffusion equation without considering the surface layer. If fits were poor, the surface layer was include in the model, as a burst release. Results showed that surface layer resulted in a burst release of about 35% of the loaded drug for the two hydrophilic drugs, and the model did not fit the data unless the surface layer was incorporated as a burst release. For the hydrophobic drugs, there was no burst release and the model fitted the data without including the surface layer likely because of the low partition coefficient of the hydrophobic drugs in the surface layer compared to the lens. The results further confirm the presence of the high water content surface layer on the Dailies Total1® lenses.
The release profile of the burst release for hydrophilic drugs could be
therapeutically useful for antibiotics where a high dose is desirable initially. The effect of vitamin E loading—an established procedure for increasing drug release time in other commercial lenses, was also tested on the release of timolol maleate and levofloxacin. A 20% vitamin E loading was found to increase the release time of timolol and levofloxacin by a factor of 5 and 3-fold respectively, but this increase proved much less effective compared to vitamin E’s effect on other commercial silicone hydrogels. Keywords: delefilcon-A lens Dailies Total1®, water gradient, drug delivery, timolol, dexamethasone, cyclosporine, levofloxacin
3 1
1. Introduction
2
Eye drops make up approximately 90% of all formulations for ophthalmic drugs in spite
3
of low bioavailability [1]. Only about 5% of the administered drug permeates cornea, with the
4
remaining 95% reaching systemic circulation, raising the potential of toxicity in key organs [2],
5
[3]. The low bioavailability of eye drops sometimes necessitates multiple eye drops each day,
6
which can reduce compliance [4]. Researchers have proposed soft contact lenses as an alternative
7
platform for ophthalmic drug delivery to significantly increase the bioavailability compared to eye
8
drops [5]. Initial attempts explored directly soaking hydrophilic lenses in a drug solution, but found
9
that unmodified contact lenses released the drug very quickly, in the order of a few minutes to an
10
hour. Recent work in this field has focused on control release from lenses through many
11
approaches including integration of particles, surfactant or vitamin E barriers into the lenses,
12
molecular imprinting, multi-layer structure and surface modifications [6-10]. The multi-layer
13
structure on its own or in combination with other approaches listed above could offer many
14
advantages for controlling the drug release profiles. For instance, a lens with a highly crosslinked
15
surface layer could reduce the high initial rates of drug release from the contact lenses, which may
16
be desirable to minimize the possibility of toxicity. Alternatively, a weakly crosslinked layer near
17
the surface could provide an increased initial release which could also be useful for some
18
indications such as infections, which require a high drug concentrations early on, followed by
19
reduced release rates. The surface layer could also offer additional benefits such as the possibility
20
of improved lubricity. For example, Alcon released a new lens ‘water-gradient’ lens in 2013
21
(delefilcon-A lens Dailies Total1®) to increase the surface lubricity [11]. This lens consists of an
22
80 µm silicon hydrogel core surrounded by a 10 µm high-water content layer. While the core has
23
a water content of approximately 33%, the outer layer has a water content of >80% [12]. While
4 24
the motivation for the development of this lens is for a higher lubricity and user comfort, the
25
surface layer could potentially be useful for obtaining desired drug release profiles from the lenses.
26
The effect of the surface layer on release profiles is expected to depend on the physical properties
27
of the drugs, particularly hydrophobicity. The surface layer may provide a burst for hydrophilic
28
drugs due to release from the high water content surface layer, and potentially provide a barrier to
29
hydrophobic drugs reducing the very high releases at short times.
30
Besides a lubricious layer, the release of drug from a contact lens can be changed by
31
modification to the lens [13-16]. As mentioned previously, unmodified contact lenses have a fast
32
release. For many drugs, the rapid release can have toxicity concerns [17-19]. Many approaches
33
have been proposed for increasing the release duration from contact lenses without sacrificing any
34
of the critical properties. Commercial contacts can be modified by incorporation of vitamin E
35
diffusion barriers into contact lenses to increase release durations of both hydrophilic and
36
hydrophobic drugs, as well as delivery multiple drugs simultaneously [20]. Vitamin E loaded
37
lenses have shown promise in in vitro experiments and in vivo animal studies on beagle models
38
with glaucoma [21]. These studies have used multiple brands of silicon hydrogels, such as
39
ACUVUE® TruEYETM or ACUVUE® Oasys®; however, none of these lenses have an outer
40
lubricious layer, which could be useful for a burst release combined with a secondary, longer
41
release of drug compared to an unmodified lens. We then explore the effect of vitamin E
42
incorporation on the Dailies Total1® to determine whether the vitamin E approach can be
43
integrated into the water gradient lens. Additionally, we expect vitamin E to partition only into
44
the core of the lens, so results from the vitamin E loaded lenses can be further useful in
45
understanding the role of the surface film on transport.
5 46
This paper examined four drugs, timolol maleate (beta blocker for treating glaucoma),
47
levofloxacin (antibiotic), dexamethasone (corticosteroid), and cyclosporine (anti-inflammatory),
48
and their release from the Dailies Total1® lens. These drugs consist of two hydrophilic, timolol
49
maleate and levofloxacin, and of two hydrophobic, dexamethasone and cyclosporine, to examine
50
the affinity of the outer layer. These four drugs have been studied in other lenses, but not in lenses
51
with the additional outer layer [11, 22-26]. The goal of this paper is to evaluate the diffusive
52
behavior of both hydrophilic and hydrophobic molecules through the dual layer lens in order to
53
better understand the effect of the high-water content surface layer on drug transport as well as see
54
if Dailies Total1® would be a good candidate for vitamin E loading as vitamin E loaded lenses
55
approach clinical human trials and eventually commercialization.
56
2. Materials and methods
57
2.1 Materials
58
Dailies Total1® lenses (diopter -8.00, delefilcon A, diameter 14.1mm) from Novartis were
59
used in this study. Timolol maleate (≥98%), levofloxacin (≥98%), and dexamethasone (≥98%)
60
were purchased from Sigma-Aldrich Chemicals (St. Louis, MO). Cyclosporine A (≥99%) was
61
purchased from LC Laboratories (Woburn, MA). Phosphate Bufferered Saline 1x without calcium
62
and magnesium (PBS) was purchased from Mediatech, Inc. (Manassas, VA). Ethanol (200 proof)
63
and Vitamin E (DL-alpha tocopherol, >96%) were purchased from Sigma-Aldrich. All chemicals
64
were used as received without further purification. Sodium Chloride was purchased from Fisher
65
Scientific.
66
2.2 Drug Solution Preparation
67
All drugs explored here are powders at room temperature. To maintain stability, the solid
68
drug, levofloxacin and dexamethasone were stored in a refrigerated at 4⁰C, cyclosporine A was
6 69
stored at -20⁰C, and timolol was stored at room temperature. All drug solutions were prepared by
70
weighing the mass (Denver Instrument, M-220D) and mixing with the required volume of PBS
71
(pH=7.4). The hydrophilic drugs dissolve easily but the hydrophobic drugs required longer stirring
72
times for complete dissolution (Table 1). Cyclosporine A and dexamethasone solutions were stored
73
in refrigerator in vials covered by aluminum foil to protect from degradation by long exposure to
74
ultraviolet light. Cyclosporine A was made at 25 μg/mL [26]. The heat of solution of cyclosporine
75
A is highly exothermic, allowing for solubility to increase with decreasing temperature. This
76
allows for this higher concentration of drug to be dissolved [27].
77
2.3 Drug Loading
78
The Dailies Total1® lenses were removed from their blister packs, rinsed with de-ionized
79
(DI) water, dabbed with a Kimwipe, and then placed in PBS overnight (12 hours) for storage. The
80
lens was then removed from the PBS, dabbed again with a Kimwipe, and placed in the drug
81
solution. The stock solution (Table 1) was used without further dilution except for cyclosporine
82
A, which was diluted to a drug concentration of 0.015 mg/mL to ensure that the solution was below
83
the solubility limit and would not experience any precipitation of drug.
84
The uptake of dexamethasone and cyclosporine could be monitored via UV-vis
85
spectrophotometry, allowing for determining when the lens reached equilibrium, which was
86
assumed after no change was detected in the loading concentration after 24 hours. The time the
87
lens reached 99.9% of this final concentration is taken as the equilibrium time. This point occurred
88
at approximately 13 and 30 hours for dexamethasone and cyclosporine respectively. The loading
89
times were roughly double of these equilibrium times to be sure that equilibrium can be assumed.
90
The uptake solutions for timolol and levofloxacin are too high to be measured for uptake, and the
91
small change in concentration would be difficult to read with dilutions. Previous studies of
7 92
hydrophilic drugs have used 24 hours as a benchmark for loading timolol maleate and levofloxacin
93
into contact lenses [22]. This loading duration was used for this study, and was found to be justified
94
when the release duration was much lower than 24 hours. The durations of the drug loading step
95
for each drug are listed in Table 2.
96
2.4 Drug Release
97
After the appropriate loading time, the lenses were removed from the solution, dabbed with
98
a Kimwipe to remove drug solution off the surface, and inserted into a blank 2 mL of PBS
99
(pH=7.4). Releases were run at ambient temperature. At specific time intervals, about 1.5 mL of
100
the release medium were withdrawn from the sample and placed into a quartz cuvette. The cuvette
101
was monitored using a UV-vis spectrophotometer (Thermospectronic Genesys 10 UV). The
102
absorbance was measured over a range of wavelengths, 270-315nm for timolol maleate, 265-
103
310nm for levofloxacin, 220-268nm for dexamethasone, and 208-220nm for cyclosporine A. After
104
measuring, the withdrawn solution was returned to the sample, so that the same solution was
105
maintained throughout the duration of the release.
106
2.5 Vitamin E Loading of Lenses
107
Commercial Dailies Total1® lenses were rinsed soaked in deionized water for 15 minutes
108
and then rinsed again with deionized water. The lenses were then soaked in a 3mL 44mg/mL
109
vitamin E-ethanol solution for 24 hours, which was determined to be adequate for equilibrium to
110
be reached between the lens and the solution. After the 24 hour period, the lenses are removed
111
from solution and left to dry for an additional 24 hours. After the drying period, the lenses were
112
rehydrated in PBS for 3 hours before being inserted into drug solution for uptake. The release of
113
drug from vitamin E loaded lenses followed the same procedure as unmodified lenses.
114
2.6. Transmittance measurement contact lens
8 115
The transmittance of Vitamin E laden lenses was measured using UV–vis spectrophotometer
116
(Thermospectronic Genesys 10 UV). The lenses were hydrated by soaking in PBS overnight, then
117
mounted on the outer surface of a quartz cuvette. The cuvette was placed in the spectrophotometer
118
and the transmittance values were measured at wavelengths ranging from 200 nm to 700 nm.
119
2.7 Ion Permeability measurement of contact lens
120
Lenses were soaked in 5 mL of a 1 M NaCl/DI H2O solution for 1 hour. Lenses were then
121
placed in 200 mL of DI H2O and monitored with a conductivity meter (OAKTON® CON 450).
122
The solution was constantly stirred at 100 rpm to keep solution well-mixed. Conductivity was
123
converted to molar concentration by measuring the conductivity of a known NaCl calibration
124
solution and using it as a conversion factor.
125
2.8 Diameter measurement of contact lens
126
Lenses were placed in a PBS solution and imaged with a digital camera. Images included
127
a ruler to determine the length per pixel ratio. Images were then analyzed in ImageJ to determine
128
diameters.
129
2.9 Data Analysis and Modeling
130
The collected spectra of release experiments were compared to a reference spectra to
131
determine the drug concentration. The measurement and the reference were compared in a Matlab
132
program using the ‘fminsearch’ function to give the ratio that gives the best fit between the two.
133
The wavelength range was used rather than a single point to ensure that there were no additional
134
absorbance contribution from any other components as well as ensuring that the drug spectra did
135
not change over the course of the experiment.
136
The ratio calculated from the Matlab program is then used to calculate the concentration of
137
the release medium. These concentration can then be multiplied by the release volume to determine
9 138
mass released. These mass released values can be divided by total mass loaded in the lens to give
139
percent release, which is the value used in plots of the releases.
140
The two main values used to quantify releases are partition coefficient, K, defined as the
141
ratio of the drug concentration in the gel and the concentration in the aqueous phase at equilibrium,
142
and diffusivity, D, which describes the resistance in the lens to the movement of drug. Partition
143
coefficient can be calculated from the equilibrium values of drug loading and release, and is
144
discussed in more detail in section 3.1 Diffusivity must be found by fitting a mathematical model
145
to the transient release data and minimizing the sum of squared error via Matlab ‘fminsearch,’
146
which is discussed in section 3.2 and 3.3. These sections describe a single layer model, a dual layer
147
with burst release model, and a numerical model for non-perfect sink conditions.
148
For the model fits, a correlation constant was calculated comparing the model value to the
149
experimental value. This value will be used when comparing different models to the experimental
150
data.
151
3. Results and Discussion
152
3.1 Partition Coefficient
153
The initial and final concentrations of the dexamethasone and cyclosporine A loading
154
solutions were measured to determine the amount of drug loaded into the lens (Table 4). The
155
concentration in the loading solution does not change significantly for the hydrophilic drugs so the
156
mass of the drug loaded in the lens could not be determined from the loading step. The amount of
157
drug taken up by the lens can be used to calculate the partition coefficient. The values of partition
158
coefficient can be obtained from both the loading and the release experiments. For the loading
159
experiment the partition coefficient can be calculated by
160
𝐾=
𝐶𝑔,𝑓 𝐶𝑙,𝑓
=
𝑉𝑙 (𝐶𝑙,𝑖 −𝐶𝑙,𝑓 ) 𝑉𝑔 𝐶𝑙,𝑓
(1)
10 161
where Vl and Vg are the volumes of the loading solution and the fully hydrated gel, respectively,
162
and Cg,f, Cl,i and Cl,f are the equilibrium concentrations of the drug in the gel, and the initial and
163
equilibrium concentrations in the loading solution. Eq. 1 is used for the calculation of the partition
164
coefficient of dexamethasone and cyclosporine.
165
The partition coefficient of hydrophilic drugs needs to incorporate the release, as the
166
loading concentration is too high to measure and remains relatively constant during loading. The
167
volume of the lens was significantly less than the volume of the loading and release media, and
168
with a high solubility limit, hydrophilic drugs can be assumed to be loading and releasing under
169
perfect sink conditions. This assumption assumes that the lens will release all of its loaded drug,
170
or in other words, that drug loaded yields drug released. Based on these assumptions, the partition
171
coefficient for hydrophilic drugs to be calculated using the following equation based on the release data:
172
𝐾=
173
where Vr and Cr,f are the volume and final concentration of the release medium, respectively. Eq.
174
2 is used to calculate the partition coefficients of timolol maleate and levofloxacin. The calculated
175
partition coefficients are listed in Table 3.
𝐶𝑔,𝑓 𝐶𝑤,𝑓
=
𝑉𝑟 (𝐶𝑟,𝑓 ) 𝑉𝑔 𝐶𝑙,𝑓
(2)
176
The Dailies Total1® lens comprise of an 80 microns thick silicone-hydrogel core with a
177
water content of 33% and an 11±4 microns thick surface layer with a water content of about 80%
178
[12]. It should be noted that, according to the product description, the aqueous concentration in the
179
outer layer is not uniform but is rather a gradient from the water concentration of inner core that
180
increases to near 100% water at the boundary layer with the bulk fluid. The measured partition
181
coefficients represent the volume average partition coefficients of the two layers. The partition
182
coefficient of hydrophobic drugs is typically larger than that for the hydrophilic drugs in silicone-
183
hydrogels because of the absorption of the drug molecules on the polymer. The high solubility of
11 184
the hydrophilic drugs results in low adsorption on the polymer, which results in a partition
185
coefficient comparable to the water content of the gel. The measured partition coefficients in
186
Dailies Total1® for levofloxacin and timolol are much smaller than those for dexamethasone and
187
cyclosporine (Table 3).
188
ACUVUE® OASYS® and ACUVUE® TruEyeTM. The partition coefficient for the Dailies
189
Total1® are of the same magnitude as the compared lenses, although the lens more closely matches
190
the hydrophobic drug behavior of TruEyeTM.
Table 3 also shows values of two other silicone hydrogel lenses,
191
Since the Dailies Total1® lens contains two distinct regions, the measured partition
192
coefficient is a combination of two separate partition coefficients. Assuming φ to be the volume
193
fraction of the surface layer based upon the ratio of thicknesses of the layers, or approximately
194
0.216 for Dailies Total1®, the partition coefficient can be described as
195
𝐾 = 𝐾1 (1 − 𝜑) + 𝐾2 𝜑
196
where K1 and K2 are the partition coefficient of the interior hydrogel and surface layer respectively.
197
As the surface layer has a high water-content, hydrophilic drugs with a low affinity for the polymer
198
matrix will mostly be in the water phase of the surface-film, matching the concentration of the
199
bulk solution. This assumption simplifies Eq. 4 by assuming K2=1 to give
200
𝐾 = 𝐾1 (1 − 𝜑) + 𝜑
201
For hydrophobic drugs, the low solubility of drugs in the aqueous phase suggests low drug
202
partitioning into the surface layer. As K1>> 𝜑 for hydrophobic drugs, this term can be ignored and
203
𝐾 = 𝐾1 (1 − 𝜑)
204
Discussion for the two region partition coefficients for timolol and levofloxacin will continue on
205
in the section on the burst release model.
206
3.2 Diffusivity
(3)
(4)
(5)
12 207
The release profile of all four drugs is shown in Figure 1, and a smaller time scale release
208
of timolol and levofloxacin are shown in Figure 2. These graphs are plotted as percent released,
209
which is the measured mass released divided by the total mass released. Timolol maleate and
210
levofloxacin, both highly hydrophilic drugs, reached 90% drug release within 15 to 20 minutes.
211
Dexamethasone and cyclosporine A, both hydrophobic drugs, had much longer release hours,
212
reaching 90% release at approximately 7 and 15 hours respectively. The slower diffusivity of the
213
hydrophobic drugs can be attributed to the higher partition coefficient of the drugs. The silicon
214
hydrogel used in contact lenses is a biphasic system, with hydrophilic and hydrophobic regions.
215
Drug inside the contact lens is either absorbed in the aqueous phase of the lens or adsorbed onto
216
the surface of the polymer matrix. While this affects the partition coefficient, as previously
217
discussed, the phase of the drug also affects its release time. After reaching equilibrium inside of
218
the loading solution, the drug inside of the lens also reaches an equilibrium between the adsorption
219
and desorption of drug on the polymer matrix. Upon release, drug exits the primarily through the
220
aqueous phase of the gel. As the aqueous concentration drops, the adsorption equilibrium is shifted,
221
and drug begins to desorb faster into the aqueous phase. This equilibrium between the adsorbed
222
and free drug is rapid, but the adsorbed drug must desorb to diffuse or diffuse along the surface
223
which is typically slower than bulk diffusion, thus reducing the flux of the drug, leading to
224
increased release duration. The diffusivity of a drug in the bi-phasic lens is a combination of the
225
diffusivities of the two different states, bulk diffusion of the free drug and surface diffusion of the
226
adsorbed drug. Considering these two fluxes separately in the convection diffusion equation yields
227
the following,
228
𝜕𝑐 𝜕𝑡
=
𝑓𝑎𝑞 𝐷𝑓 𝜕2 𝑐 𝐾
𝜕𝑦
+ 2
(𝐾−𝑓𝑎𝑞 )𝐷𝑠 𝜕2 𝑐 𝐾
𝜕𝑦 2
= 𝐷𝑒𝑓𝑓
𝜕2 𝑐 𝜕𝑦 2
(6)
13 229
where faq is the volume fraction of the aqueous phase, and Df and Ds are the diffusivities of drug
230
in solution and on the surface respectively. The effective overall diffusivity can be defined as the
231
combination of the two diffusivities based on the phase’s volume fraction of the lens, i.e.,
232
𝐷𝑒𝑓𝑓 =
𝑓𝑎𝑞 𝐷𝑓 +(𝐾−𝑓𝑎𝑞 )𝐷𝑠 𝐾
(7)
233
When release experiments are fitted to diffusion control model, the fitted diffusivity is the
234
effective diffusivity, which explains why the release durations for the hydrophobic drugs are
235
longer than those for hydrophilic drugs.
236
3.3. Models for Drug Release
237
To determine whether the surface layer impacts drug transport, the experimental data was
238
first fitted to a model that neglects the surface layer. The diffusion-control release from the
239
silicone-hydrogel core can be described by the 1-D diffusion equation,
240
𝜕𝐶 𝜕𝑡
=𝐷
𝜕2 𝑦 𝜕𝑦 2
(8)
241
where C is drug concentration in the gel, D is the effective diffusivity, t is time, and y is the
242
transverse coordinate (y = 0 is the center of the lens). The above equation implicitly neglects radial
243
transport because of the much larger radius compared to the thickness, and also assumes that the
244
transport can be described by using an average film thickness h instead of a position dependent
245
thickness. The diffusion equation can be solved subject to the following boundary and initial
246
conditions 𝜕𝐶
(𝑡, 𝑦 = 0) = 0
(9)
248
𝐶(𝑡, 𝑦 = ℎ) = 𝐾𝐶𝑟
(10)
249
𝐶(𝑡 = 0, 𝑦) = 𝐶𝑖
(11)
247
𝜕𝑦
14 250
where Ci is the initial drug concentration of the lens, h is half the thickness of the silicone-hydrogel
251
core, K is the partition coefficient and Cr is the drug concentration in the release medium. The first
252
boundary condition assumes symmetry at the center of the lens, while the second assumes
253
equilibrium at the boundary between the lens and the release medium. The concentration in the
254
release medium can be determined through a mass balance that equates the drug released by the
255
lens to accumulation in the fluid, i.e.,
256
𝑉𝑟
257
where As is the total surface area of the lens, including both sides.
𝑑𝐶𝑟 𝑑𝑡
𝜕𝐶
= −𝐷𝐴𝑠 𝜕𝑦|
(12)
𝑦=ℎ
258
For hydrophilic drugs, the partition coefficient is sufficiently small so a perfect sink
259
assumption can be used, which implies that the concentration in the release medium is negligible.
260
This assumption is reasonable in the release experiments because the volume of the release
261
medium (2 mL) was much larger than the volume of the lens (approximately 30μL) and the
262
partition coefficient was small. Under perfect sink assumption, the concentration in the lens and
263
the release medium are given by the following equations
264
𝑖 𝐶 = ∑∞ 𝑛=0 (2𝑛+1)𝜋 cos (
(−1)𝑛 4𝐶
(2𝑛+1)𝜋 2ℎ
𝑦) 𝑒
(2𝑛+1)2 𝜋2 16 𝐴𝑠 ℎ𝐶𝑖 − 𝐷𝑡 ∞ 4ℎ2 ∑𝑛=0 𝑒 𝑉𝑟 (2𝑛+1)2 𝜋 2
−
(2𝑛+1)2 𝜋2 𝐷𝑡 4ℎ2
(13)
265
𝐶𝑟 =
266
where As is the surface area of the lens, C is the concentration inside of the lens, Cr is the
267
concentration in the release medium, h is half the thickness of the lens, Vr is the volume of the
268
release medium, n is an integer, D is diffusivity, and t is time. This analytical solution can then be
269
fitted to the data by using the ‘fminsearch’ function to vary D, diffusivity, to minimize the error.
270
Concentration can be converted to percent released by dividing by the final concentration value
(14)
15
271
𝐶𝑟 (𝑡) 𝐶𝑟 (𝑡→∞)
= 𝑃𝑒𝑟𝑐𝑒𝑛𝑡 𝑅𝑒𝑙𝑒𝑎𝑠𝑒𝑑 = 1 −
8 𝜋2
∑
1 ∞ 𝑛=0 (2𝑛+1)2
𝑒
(2𝑛+1)2 𝜋2 𝐷𝑡 4ℎ2
−
(15)
272
where Cr(t→∞) is the final concentration of the release medium. This model is used to determine
273
the diffusivities of the non-burst release models for all four drugs. The initial guess for diffusivity
274
fitting was obtained by fitting the short time release profile to the following equation,
275
𝐶𝑟 (𝑡) 𝐶𝑟 (𝑡→∞)
=
2 ℎ
𝐷
√ (𝑡)1/2 𝜋
(16)
276
This model is valid when 𝑡 < ℎ⁄4𝐷𝑡 . The single layer models for timolol and levofloxacin are
277
shown in Figure 4 and Figure 7, and have correlation coefficients of 0.9643 and 0.9484 respectively
278
(Table 5).
279
3.3.1 Burst Release
280
For timolol maleate and levofloxacin, the best fits consistently undrepredict the fraction
281
release in the short time range, as seen in Figure 6. Furthermore, the short term data can be fitted
282
linearly to sqrt(t) but only with a non-zero intercept, suggesting a very rapid release of a fraction
283
of the drug, as the initial concentration of the release medium should be zero, giving a zero
284
intercept. To have a non-zero intercept then suggests a rapid, nearly instantaneous release. Since
285
Dailies Total1® contact lens has two distinct layers, the transport can be described by a two layer
286
system to account for this rapid, or burst release. The effective diffusivity in the outer layer in the
287
Dailies Total1® contact lens will likely be much higher than in the inner core because of the high
288
water content. Assuming that the diffusivity in the surface layer is comparable to that in the
289
solution, the time for release from the surface layer can be approximated to be about a second,
290
which is far too rapid for analytical measurements. Because of this rapid release of the timolol
291
maleate and levofloxacin, it is possible to model these releases as instantaneous release of the
292
portion of the drug loaded in the surface layer, followed by a diffusive-release from the core. The
16 293
extend of the burst release was obtained by fitting the data but the initial guess was assumed to be
294
21.6% based on the volume fraction of the surface layer compared to the entire lens [8]. To model
295
the remaining drug release, the mass of the burst is subtracted from subsequent measurements, and
296
the modified data points are then fitted to minimize the error. All of this is completed in Matlab
297
using a modified version of Equation 14 16𝑀(1−𝑓𝑚𝑜𝑑𝑒𝑙 ) − ∑∞ 𝑛=0 𝑉 (2𝑛+1)2 𝜋2 𝑒
(2𝑛+1)2 𝜋2 𝐷𝑡 4ℎ2
𝑀
298
𝐶𝑟 =
299
where fmodel is the volume fraction of the lens responsible for burst release and M is the total mass
300
released. fmodel can be taken to be a volume fraction as this model assumes an similar concentration
301
across both layers of the lens.
𝑤
+ 𝑓𝑚𝑜𝑑𝑒𝑙 𝑉
𝑤
(17)
302
The burst model plots for timolol and levofloxacin in Figure 5 and Figure 8 respectively.
303
As seen in Table 5, the correlation coefficients using the burst release are increased to 0.9966 and
304
0.9921 for timolol and levofloxacin respectively, improved from the single layer model. Compared
305
to lenses studied in other papers, such as ACUVUE® lenses (Table 7). Dailies Total1® has a much
306
faster release duration, suggesting that the material used in this lens offers a much lower resistance
307
to diffusion compared to other commercially available hydrogels [11, 22, 24-26]. When comparing
308
the drug release times, the order from fastest to slowest falls in order of increasing molecular
309
weight. While this mass difference offers an explanation for the difference between timolol
310
maleate and levofloxacin as well as dexamethasone and cyclosporine, the effect of molecular
311
weight is smaller than the effect of the affinity of the drug towards water, as evidenced by the ~40
312
times increase in release duration between levofloxacin and dexamethasone, both of which have
313
similar molecular weights. This ratio is comparable to the ratio of the partition coefficients, which
314
suggests that the reduced diffusivity of dexamethasone is due to binding, and that the surface
315
diffusivity of the bound dexamethasone molecules is low.
17 316
No burst release was observed in either the dexamethasone or cyclosporine releases. This
317
lack of a burst release supports the notion of low partitioning into the aqueous phase of the lens
318
and that the outer layer, with its high water content, would have a much smaller amount of drug
319
than the inner core. The lack of a burst release for the hydrophobic drugs also validates that the
320
observed burst release of the hydrophilic drugs is not due to excess drug left on the surface when
321
removing the lens from the loading solution. If this situation were true, then the hydrophobic drugs
322
would have also shown a large initial release. The surface layer also does not act as a barrier to
323
the drug transport because even though the partition coefficient is low in this layer, the diffusivity
324
is likely very large due to the high water content, and thus the product KD for this layer is still
325
much larger than that for the lens core. Values for KD of the inner core are shown in Table 8. The
326
percentage value for the burst release for hydrophilic drugs is also of interest. The outer layer
327
composes approximately 20% of the lens’s volume. The similarity of magnitude suggests that the
328
initial burst is exclusively from the outer layer. The fraction of the burst release can be used to
329
evaluate the partition coefficients calculated in Eq. 3 and 4. These can be expressed as
330
𝑓𝑐𝑎𝑙𝑐 = 𝐾
331
And if K2 is assumed to equal 1
332
𝑓𝑐𝑎𝑙𝑐 = 𝐾
333
These two equations can show if the treatment of the outer layer as water predicts the behavior of
334
the burst release. Calculations for fcalc for timolol and levofloxacin are shown in Table 6 and are
335
compared to fmodel from the burst release model of Eq. 17. The calculations assuming a K2=1
336
give a fractional burst release of 0.13 compared to the model predicted 0.16±0.1 for timolol and
337
0.30 versus 0.2±0.2 for levofloxacin, which is a reasonable agreement.
338
3.3.2 Numerical Model for Hydrophobic Drugs
𝐾2 𝜑 (1−𝜑)+𝐾 1 2𝜑
𝜑 1 (1−𝜑)+𝜑
(18)
(19)
18 339
When comparing the values of loading and release in Table 4, it can be seen that a sizeable
340
portion of the drug remains in the lenses after a release without replacing the release medium. In
341
order to model the release in terms of percent of loaded drug released (Figure 3), a non-perfect
342
sink must be assumed, which requires a numerical model. An intrinsic finite difference method
343
was used in Matlab to model the numerical equation
344
𝑡+1 𝑡+1 𝐶𝑦𝑡+1 − 𝐶𝑦𝑡 = (∆𝑦)2 /∆𝑡 (𝐶𝑦+1 − 2𝐶𝑦𝑡+1 + 𝐶𝑦−1 )
345
where t is time, y is position from center of lens, C is drug concentration, D if effective diffusivity,
346
and Δy and Δt are the node step and time step respectively. This numerical model used the mass
347
balance of Eq. 12 to set its boundary conditions, the initial concentration in the lens were
348
determined from the loaded drug, and the initial concentration in the release medium was set to
349
zero. This numerical model was allowed to optimize diffusivity, with the initial input coming from
350
fitting Eq. 15; however, no sizeable change (<1%) in diffusivity was found by switching to the
351
numerical model. The fits of the model are shown in Figure 9 and Figure 10 and is in agreement
352
with the experimental data, with a correlation coefficient of 0.9869 and 0.9943 for dexamethasone
353
and cyclosporine. As these fits assume a single layer, their accuracy suggests that the surface layer
354
does not significantly impact the drug transport for the hydrophobic drugs.
355
3.4 Vitamin E incorporation
𝐷
(20)
356
Vitamin E incorporation has been explored as an approach to increase the release duration
357
of drugs through creation of diffusion barriers in multiple brands of commercial contact lenses.
358
Previous studies have examined the effect of the swelling of the lens due to ethanol and the
359
integration of vitamin E [20, 22, 24-26]. These studies found that after returning the lens to de-
360
ionized water or PBS solutions, the 20% vitamin E lens returned within 5% of its original diameter.
361
Lens parameters such as ion permeability, and oxygen permeability were found to be above
19 362
required minimum values after loading at 30% vitamin E or lower, as shown in Table 9 [22]. This
363
maintaining of the lens properties has allowed lenses modified with vitamin E to be used in animal
364
studies and approved for Phase I human studies.
365
Vitamin E loading increases the hydrophobic fraction of the silicon hydrogel. Highly
366
hydrophilic molecules such as timolol or levofloxacin have difficulty partitioning into a vitamin E
367
phase, and as such, must diffuse around the vitamin E, increasing their release time. The vitamin
368
E barriers are expected to form at the interface of the hydrophilic and silicone phases in the lens
369
matrix, and so incorporation of vitamin E in the lens can be used as an indirect approach for
370
exploring the microstructure. The concentration of vitamin E in ethanol was selected based upon
371
previous studies, which used 40-45 mg/mL vitamin E loading to achieve a 20% loading. The dry
372
weight of the Dailies Total1® lenses increased by 20±2% compared to the control by soaking in
373
the ethanol containing 44mg/mL vitamin E, which is comparable to the vitamin E loading achieved
374
in other commercial lenses. This increase can be ascribed to the mass of vitamin E loaded in the
375
lens. The weight gain in the lens is proportional to the degree of swelling in ethanol. The vitamin
376
E loaded lenses remain transparent, which suggests that the aggregates are nanosized.
377
The release of timolol and levofloxacin vitamin E loaded Dailies Total1® lenses can be
378
seen in Figure 11 and Figure 12 respectively. Vitamin E incorporation increases the release
379
duration of timolol and levofloxacin to about an hour, or roughly a 5-fold and 3-fold increase in
380
release time which can be ascribed to the formation of the diffusion barriers in the core of the lens.
381
The partition coefficient decreases for both timolol and levofloxacin to 1.43 and 0.47 respectively,
382
which is probably due to the hydrophobic nature of the vitamin E; however, the high solubility of
383
both of these drugs means that a higher drug loading concentration would compensate in the loss
384
of the partitioning onto the lens. The release profiles from the vitamin E loaded lenses exhibit burst
20 385
release as well, but the magnitude is slightly reduced comparable to that in the control lens. The
386
slight reduction could be due to the reduced drug loading in the core. While this increase in release
387
time is promising for drug delivery, the magnitude of increase achieved with vitamin E loading is
388
much larger in other lenses such as ACUVUE® OASYS®, making these other lenses more
389
effective in delivering larger dosages of drug to the anterior of the eye, as the rapid release from
390
Dailies Total1® could lead to toxicity concerns. However, for antibiotics such as levofloxacin, the
391
burst release, followed by an additional hour long release, might prove to be highly effective.
392
3.5 Effect of vitamin E on contact lens
393
Figure 13 shows that the decrease in transmittance due to vitamin E loading was almost
394
exclusively in the UV region, with the visible range maintaining a transmittance of greater than
395
88%. Figure 14 shows a digital image of both a control and modified lens, showing both the
396
maintained transmittance in the visible light range as well as the similar size of the two lenses.
397
Table 9 shows that the vitamin E loading yielded a 2.6% increase in lens diameter, putting in line
398
with other commercial lenses which see an increase of 3-4% [22]. This small increase means that
399
the curvature of the lens should remain largely unaffected. The hydrophobic nature of vitamin E
400
decreased the ion permeability of the Dailies Total1® lens, as seen in Table 9.
401
Oxygen permeability was not evaluated for Dailies Total1® lenses. However, past studies
402
have looked at other commercial lenses such as ACUVUE® OASYS® and O2 OptixTM showed
403
that vitamin E loading led to a small decrease in oxygen permeability but that the value was still
404
higher than the required 70 barrer to prevent hypoxia [22]. As Dailies Total1® has a higher oxygen
405
permeability than either of these lenses at a value of 156 barrer, it can be expected to stay above
406
the minimum required value at 20% vitamin E loading. Another lens parameter that was not
407
characterized was protein adherence. Future study will be needed to quantify vitamin E’s effect,
21 408
but the protein adherence should decrease as the diffusion rate of the proteins should decrease in
409
the lens.
410
4. Conclusions
411
The presence of the thin high water content surface layer has a significant impact on the drug
412
release profiles for hydrophilic drugs. The drug incorporated in the surface layer diffuses out
413
rapidly for both timolol maleate and levofloxacin. The duration of this rapid release was far too
414
short for measurements so it was included in the transport model as a burst release. The
415
experimental data showed a good fit with a diffusion control model, but only after the release
416
from the surface layer was included as a burst. The partition coefficient of the hydrophilic drugs
417
in the outer layer is close to one which is expected due to the very high water content. The
418
presence of the burst further validates the reported structure of the high water content surface
419
film in Dailies Total lenses. The burst release could be clinically useful for antibiotics, but may
420
be undesirable for other indications. The absence of the initial burst for dexamethasone and
421
cyclosporine A show that the outer layer has very low affinity for the hydrophobic drugs due to
422
the very low polymer fraction in the layer. Overall, the release duration from the Dailies Total1®
423
lens is less compared to other commercial lenses such as ACUVUE® OASYS® and ACUVUE®
424
TryEye®. Vitamin E incorporation can increase the release duration and decrease the initial burst
425
slightly. The release duration of the hydrophilic drugs may be far too short, but the release
426
duration for hydrophobic drugs is sufficient as a daily disposable modality. Studies on the effect
427
of vitamin E loading showed it to have minimal effect on transmittance and diameter of the lens,
428
while ion permeability was kept above the required limit for eye movement. Future work is
429
needed to characterize the effect of vitamin E loading on Dailies Total1® lenses oxygen
22 430
permeability and protein adherence before human use, but previous work on other commercial
431
contact lenses indicates that lens parameters should still be within required limits. 5. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems. Prog Retin Eye Res 1998;17(1):33–58 Mitra AK, editor. Ophthalmic drug delivery systems. New York, NY: Marcel Dekker, Inc.; 1993. p. 60 Segal P. Pumps and timed release. FDA Consumer Magazine; October 1991 N.P. Jones, R.J. Postlethwaite, J.L. Noble, Clearance of corneal crystals innephropathic cystinosis by topical cysteamine 0.5-percent, Br. J. Ophthalmol. 75 (1991) 311–312. Chi-Chung Li and Anuj Chauhan, Modeling Ophthalmic Drug Delivery by Soaked Contact Lenses, Ind. Eng. Chem. Res. 2006, 45, 3718-3734. Venkatesh S, Sizemore SP, Byrne ME. Biomimetic hydrogels for enhanced loading and extended release of ocular therapeutics. Biomaterials 2007;28:717–24. Hiratani H, Alvarez-Lorenzo C. The nature of backbone monomers determines the performance of imprinted soft contact lenses as timolol drug delivery systems. Biomaterials 2004;25:1105–13. Hiratani H, Mizutani Y, Alvarez-Lorenzo C. Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities. Macromol Biosci 2005;5:728–33. Alverez-Lorenzo C, Hiratani H, Gomez-Amoza JL, Martinez-Pacheco R, Souto C, Concheiro A. Soft contact lenses capable of sustained delivery of timolol. J Pharm Sci 2002;91:2182–92. Hiratani H, Alvarez-Lorenzo C. Timolol uptake and release by imprinted soft contact lenses made of N, Ndiethylacrylamide and methacrylic acid. J Control Release 2002;83:223–30. Pruitt J, Bauman E. The Development of Dailies Total1 Water Gradient Contact Lenses, Optometric Management 2013:9 T.J. Dursch, D.E. Liu, Y. Oh, C.J. Radke, Fluorescent solute-partitioning characterization of layered soft contact lenses, Acta Biomaterialia 2015:15:54-48 Hillman JS. Management of acute glaucoma with pilocarpine-soaked hydrophilic lens. Br J Ophthalmol 1974;58:674–9. Ruben M, Watkins R. Pilocarpine dispensation for the soft hydrophilic contact lens. Br J Ophthalmol 1975;59:455–8. Arthur BW, Hay GJ, Wasan SM, Willis WE. Ultrastructural effects of topical timolol on the rabbit cornea – outcome alone and in conjunction with a gas permeable contact-lens. Arch Ophthalmol 1983;101:1607–10. Wilson MC, Shields MB. A comparison of the clinical variations of the iridocorneal endothelial syndrome. Arch Ophthalmol 1989;107:1465–8. Schultz CL, Nunez IM, Silor DL, Neil ML. Contact lens containing a leachable absorbed material. US Patent No. 5723131, 1998. Schultz CL, Mint JM. Drug delivery system for antiglaucomatous medication. US Patent No. 6410045, 2002. Karlgard C,Wong NS, Jones L, Moresoli C. In vitro uptake and release studies of ocular pharmaceutical agents by silicon-containing and p-HEMA hydrogel contact lens materials. Int J Pharm 2003;257:141–51. Hsu, K.H., Fentzke, R.C., Chauhan, A., 2013. Feasibility of corneal drug delivery of cysteamine using vitamin E modified silicone hydrogel contact lenses. Eur J Pharm Biopharm 85, 531-540. Peng, CC, A. Ben-Shlomo, E. O. Mackay, C. E. Plummer, and A. Chauhan. "Drug Delivery by Contact Lens in Spontaneously Glaucomatous Dogs." Current Eye Research 37.3 (2012): 204-11. Cheng-Chun Peng, Jinah Kim, Anuj Chauhan, Extended delivery of hydrophilic drugs from siliconehydrogel contact lenses containing Vitamin E diffusion barriers, Biomaterials 31 (2010) 4032–4047 Jinah Kim, Anuj Chauhan, Dexamethasone transport and ocular delivery from poly(hydroxyethyl methacrylate) gels, International Journal of Pharmaceutics 353 (2008) 205–222 Paradiso, P., A. P. Serro, B. Saramago, R. Colaço, and A. Chauhan. "Controlled Release of Antibiotics From Vitamin E Loaded Silicone-Hydrogel Contact Lenses." Journal of Pharmaceutical Sciences 105.3 (2016): 1164-172.
23 25. Jinah Kim, Cheng-Chun Peng, Anuj Chauhan, Extended release of dexamethasone from silicone-hydrogel contact lenses containing vitamin E, Journal of Controlled Release 148 (2010) 110–116 26. Peng, CC, and A. Chauhan. "Extended Cyclosporine Delivery by Silicone-hydrogel Contact Lenses." Journal of Controlled Release 154.3 (2011): 267-74 27. Ismailos, G., Reppas, C., Dressman, J. B. and Macheras, P. (1991), Unusual solubility behaviour of cyclosporin A in aqueous media. Journal of Pharmacy and Pharmacology, 43: 287–289. 28. Nicolson P, Baron RC, Chabrecek P, Court J, Domscheke A, Griesser HJ, et al.Extended wear ophthalmic lens. US Patent No. 5760100, 1998. 29. Holden B, Mertz G. Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses. Invest Ophthalmol Vis Sci 1984;25:1161–7.
Tables & Figures Table 1: Composition, and preparation and storage conditions for the stock solutions Drug Timolol maleate Levofloxacin Dexamethasone Cyclosporine A
Stock Concentration (mg/mL) 1.5 5.0 0.05 0.025
Mixing Time (hrs) 1 1 3 24
Solution Storage Temperature (°C) Room Room 4⁰C 4⁰C
Table 2: Summary of composition and methods for the drug loading Drug
Loading Concentration (mg/mL)
Timolol maleate Levofloxacin Dexamethasone Cyclosporine A
1.5 5.0 0.05 0.015
Loading Solution Volume (mL) 3 3 4 10
Loading Time (hrs)
Solution Storage Temperature (°C)
24 24 48 72
Room Room 4⁰C 4⁰C
Table 3: Partition Coefficients in Dailies Total and comparison with previously reported partition coefficients in other commercial contact lenses Drug Dailies Total1® Partition 1-Day ACUVUE® ACUVUE® Coefficient TruEyeTM Oasys® Timolol maleate 1.60±0.11 --1.661 Levofloxacin 0.78±0.07 0.74±0.112 0.58±0.092 Dexamethasone 43.46±3.74 --105.703 Cyclosporine 160.80±7.55 31.60±10.34 485.0±30.24 1-[23], 2-[25], 3-[24], 4-[26] Data is shown as Mean ± Std (N = 6)
24 Table 4: Mass Uptake and Release of Dailies Total1® Loading Molecular Weight1 Drug Conc. (g/mol) (mg/mL) Timolol maleate 1.5 316 Levofloxacin 5.0 361 Dexamethasone 0.05 392 Cyclosporine 0.015 1202 1-From manufacturer Data is shown as Mean ± Std (N = 6)
Mass Uptake (μg)
Mass Released (μg)
----80.0±2.2 48.3±2.9
37.1±2.0 60.6±4.4 35.4±0.5 8.4±0.9
Table 5: Diffusion Coefficient (units m2/s) and Correlation Constants for different models: Single Correlation Layer Constant Diffusivity R2 Timolol 1.79E0.9643 maleate 12±8E-14 Levofloxacin 1.77E0.9484 12±2E-14 Dexamethasone --Cyclosporine --Data is shown as Mean ± Std (N = 6) Drug
Burst Release Diffusivity 1.53E12±8E-14 1.25E12±2E-14 -----
Correlation Constant R2
Numerical, NonPerfect Sink Diffusivity
0.9966
---
0.9921
--9.98E-14 3.19E-14
Table 6: Burst Release Partition Coefficient and fractional releases Drug K K1 (K2=1)1 f calc2 f model3 K1 (K2≠1) K2 Timolol 1.60 1.77 0.13 0.16 1.71 1.18 Timolol (20% vitamin E) 1.43 1.55 0.15 0.16 1.53 1.07 Levofloxacin 0.78 0.63 0.30 0.25 0.68 0.82 1-K1 indicates inner core, K2 indicates outer core; 2-From Eq. 17; 3-From Eq. 18 and 19 Table 7: Comparison of Release times (90% total mass released) Drug Dailies Total1® 1-Day Acuvue TruEye Acuvue Oasys Timolol maleate 0.2 hrs ---1.5 hrs1 Levofloxacin 0.2 hrs 33.3 hrs2 8.3 hrs2 Dexamethasone 8 hrs ---40 hrs3 Cyclosporine 18 hrs 25 hrs4 >20 days4 1-[23]; 2-[25]; 3-[24]; 4-[26]
Table 8: Calculated Permeability of inner silicone core K (inner core) D (m^2/s) KD (m^2/s) Timolol maleate 1.71 1.53E-12 2.62E-12 Levofloxacin 0.68 1.25E-12 8.50E-13 Dexamethasone 43.46 9.98E-14 4.34E-12 3.19E-14 Cyclosporine 160.80 5.13E-12
Correlation Constant R2
0.9869 0.9943
25
Table 9: Effect of vitamin E loading
Parameter Ion Permeability (mm2/min)
Minimum Value 6.00E-063
Dailies Total1® 4.92E-04
20% Vitamin E 7.94E-05
Diameter1 (cm)
---
1.412±0.007 ACUVUE OASYS®
Oxygen permeability2 (barrer)
874
120±18
1.449±0.011 20% Vitamin E 110±20
permeability2
874
O2 Optix Oxygen
(barrer)
20% Vitamin E 103±17
112±23
1- Dailies Total1® manufacturer value = 1.41 cm 2- from [22]; 1 barrer = 10-11 (cm2/s)(mLO2/mL mmHg)) 3- [28] 4- [29]
Percent Released
100%
80% 60%
Cyclosporine A
40%
Timolol Maleate Levofloxacin
20%
Dexamethasone
0% 0
5
10
15
20
25
30
Time (hr)
Figure 1: Release profile of four drugs from Dailies Total1®. Percent Release is defined as the ratio of the drug released at any time divided by the maximum mass of drug release. For hydrophilic drugs, a majority of the drug is released but for the hydrophobic drugs, a significant portion remains in the lens after equilibrium is reached. Data is shown as Mean ± Std (N = 6)
26
100%
Percent Released
80% 60% 40% Timolol Maleate
20% Levofloxacin
0% 0
0.1
0.2
Time (hr)
0.3
0.4
0.5
Figure 2: Release profiles of timolol maleate and levofloxacin. Percent release is calculated as the ratio of drug released at any time and that released at equilibrium. Data is shown as Mean ± Std (N = 6)
Percent Loaded Mass Released
27
50% 40% 30% 20% 10%
Dexamethasone Release Cyclosporine Release
0% 0
5
10
Time (hr)
15
20
25
Figure 3: Release profiles of dexamethasone and cyclosporine. The y-axis represents the ratio of drug released from the lens and that loaded in the lens during drug loading. A significant portion of the loaded drug is retained in the lens after equilibrium is reached. Data is shown as Mean ± Std (N = 6)
Percent Loaded Mass Released
28
100% 80% 60% 40% Timolol Maleate
20% Analytical Best Fit
0% 0.00
0.10
0.20
0.30
0.40
Time (hr) Figure 4: Comparison of the timolol release profiles and the best fit based on a single-layer diffusion control model under sink conditions (Eq. 15). Data is shown as Mean ± Std (N = 6).
0.50
Percent Loaded Mass Released
29
100% 80% 60% 40% Timolol Maleate
20%
Burst
0% 0.00
0.10
0.20
0.30
0.40
0.50
Time (hr) Figure 5: Comparison of the timolol release profiles and the best fit based on a diffusion control model under sink conditions including a burst release from the surface layer (Eq. 17). Data is shown as Mean ± Std (N = 6)
30
Residual Error
a
0.04 0.00
0
0.1
0.2
0.3
0.4
0.5
-0.04 -0.08
Single Layer Model Burst Release Model
-0.12
Residual Error
b
Time (hr)
0.08 0.04
0.00
0.00
0.10
0.20
0.30
0.40
0.50
-0.04 -0.08 -0.12 -0.16
Single Layer Model Burst Release Model
Time (hr)
Figure 6: Residual Error plots for fitting of the (a) timolol maleate and (b) levofloxacin experimental data with single layer model (blue) and the model after including burst (orange).
31
Percent Loaded Mass Released
100%
80%
60%
40% Levofloxacin 20% Analyticl Fit 0%
0.00
0.10
0.20
0.30
0.40
0.50
Time (hr) Figure 7: Comparison of the levofloxacin release profiles and the best fit based on a single-layer diffusion control model under sink conditions (Eq. 15). Data is shown as Mean ± Std (N = 6).
Percent Loaded Mass Released
32
100% 80% 60% 40% Levofloxacin
20% Burst Model
0% 0.00
0.10
0.20
0.30
0.40
0.50
Time (hr) Figure 8: Comparison of the levofloxacin release profiles and the best fit based on a diffusion control model under sink conditions including a burst release from the surface layer (Eq. 17). Data is shown as Mean ± Std (N = 6).
Percent Mass Loaded Released
33
50% 40% 30% 20% 10%
Non-perfect Sink Fit Dexamethasone Release
0%
0
4
8
12
16
20
Time (hr) Figure 9: Comparison of the dexamethasone release profiles and the best fit based on a numerical single-layer diffusion control model (Eq. 20). Data is shown as Mean ± Std (N = 6).
34
Percent Loaded Mass Released
20%
15%
10%
Non-perfect Sink Fit
5%
Cyclosporine Release
0% 0
5
10
15
20
25
30
35
Time (hr) Figure 10: Comparison of the cyclosporin A release profiles and the best fit based on a single-layer diffusion (Eq. 20). Data is shown as Mean ± Std (N = 6).
35
100%
Percent Released
80% 60% 40% 0% Vitamin E
20%
20% Vitamin E
0% 0.00
0.40
0.80
1.20
1.60
Time (hr) Figure 11: Effect of vitamin E incorporation on release of timolol maleate from Dailies Total1® lens. Data is shown as Mean ± Std (N = 6) for 0% vitamin E and (N=3) for 20% vitamin E.
36
100%
Percent Released
80% 60% 40% 20%
0% Vitamin E 20% Vitamin E
0%
0.00
0.40
0.80
Time (hr)
1.20
Figure 12: Effect of vitamin E incorporation on release of levofloxacin from Dailies Total1® lens. Data is shown as Mean ± Std (N = 6) for 0% vitamin E and (N=3) for 20% vitamin E.
37
100%
Transmittance
80%
60%
40% Dailies TOTAL1 20% vitamin E Loaded Dailies TOTAL1
20%
0% 200
300
400
500
600
700
Wavelength (nm) Figure 13: Transmittance spectrum of Dailies Total1® and Dailies Total1® with 20% vitamin E loading.
A
B
Figure 14: Image of unmodified (left side of image) and 20% vitamin E loaded (right side of image) Dailies Total1® with no dye (image A) and Nile blue dye (image B) for better visualization
*Graphical Abstract (for review)
Levofloxacin
100% 80%
60% 40% 20% 0% 0.00
0.10
0.20
0.30
0.40
0.50
Time (hr)
Percent Loaded Mass Released
Percent Loaded Mass Released
Timolol Maleate 100% 80% 60% 40% 20% 0% 0.00
0.10
0.30
0.40
0.50
Time (hr)
Dexamethasone…
Cyclosporine…
50%
20%
40%
Percent Loaded Mass Released
Percent Mass Loaded Released
0.20
15%
30%
10%
20%
10% 0% 0
4
8
12
Time (hr)
16
20
5%
0% 0
5
10
15
20
Time (hr)
25
30
35